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Sample records for regulating vascular pathology

  1. Regulator of calcineurin 1 mediates pathological vascular wall remodeling

    Science.gov (United States)

    Esteban, Vanesa; Méndez-Barbero, Nerea; Jesús Jiménez-Borreguero, Luis; Roqué, Mercè; Novensá, Laura; Belén García-Redondo, Ana; Salaices, Mercedes; Vila, Luis; Arbonés, María L.

    2011-01-01

    Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1−/− mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression. PMID:21930771

  2. The pathology and pathophysiology of vascular dementia.

    Science.gov (United States)

    Kalaria, Raj N

    2017-12-19

    Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. [Vascular Calcification - Pathological Mechanism and Clinical Application - . Role of vascular smooth muscle cells in vascular calcification].

    Science.gov (United States)

    Kurabayashi, Masahiko

    2015-05-01

    Vascular calcification is commonly seen with aging, chronic kidney disese (CKD), diabetes, and atherosclerosis, and is closely associated with cardiovascular morbidity and mortality. Vascular calcification has long been regarded as the final stage of degeneration and necrosis of arterial wall and a passive, unregulated process. However, it is now known to be an active and tightly regulated process involved with phenotypic transition of vascular smooth muscle cells (VSMC) that resembles bone mineralization. Briefly, calcium deposits of atherosclerotic plaque consist of hydroxyapatite and may appear identical to fully formed lamellar bone. By using a genetic fate mapping strategy, VSMC of the vascular media give rise to the majority of the osteochondrogenic precursor- and chondrocyte-like cells observed in the calcified arterial media of MGP (- / -) mice. Osteogenic differentiation of VSMC is characterized by the expression of bone-related molecules including bone morphogenetic protein (BMP) -2, Msx2 and osteopontin, which are produced by osteoblasts and chondrocytes. Our recent findings are that (i) Runx2 and Notch1 induce osteogenic differentiation, and (ii) advanced glycation end-product (AGE) /receptor for AGE (RAGE) and palmitic acid promote osteogenic differentiation of VSMC. To understand of the molecular mechanisms of vascular calcification is now under intensive research area.

  4. Color Doppler Ultrasonographic Findings of Vascular Leiomyoma: Pathologic Correlation

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    Ko, Ji Young; Koh, Sung Hye; Min, Soo Kee; Choi, A Lam; Jang, Kyung Mi; Lee, Yul; Lee, Kwan Seop; Lee, Hyun; Sohn, Jeong Hee [Hallym University Sacred Heart Hospital, Anyang (Korea, Republic of); Kim, Sam Soo [Kangwon National University College of Medicine, Chuncheon (Korea, Republic of)

    2009-12-15

    To evaluate the distribution of color flow signals on color Doppler ultrasonography of vascular leiomyomas and to correlate them with pathologic findings. We retrospectively analyzed color Doppler ultrasonographic images and pathologic slides of six vascular leiomyomas. We classified the patterns of distribution of color flow signals into localized compact cluster types and non-cluster types, and the pathologic findings into three subtypes: solid, venous and cavernous. All cases showed well-defined homogenous hypoechoic subcutaneous masses on gray-scale ultrasonography. Three cases showed localized compact cluster types on color Doppler ultrasonography, one in each subtype (solid, venous and cavernous). For the three non-cluster types, again there was on in each subtype. In addition, on pathologic analysis the zone of the localized compact cluster of color flow signals coincided with a cluster of larger, vascular caliber masses. Localized compact clusters of color flow signals on color Doppler ultrasonography were seen in 50% of our cases and correlated with a cluster of larger vascular caliber in the mass. But the pattern of distribution of color flows didn't show a correlation with pathologic type

  5. Color Doppler Ultrasonographic Findings of Vascular Leiomyoma: Pathologic Correlation

    International Nuclear Information System (INIS)

    Ko, Ji Young; Koh, Sung Hye; Min, Soo Kee; Choi, A Lam; Jang, Kyung Mi; Lee, Yul; Lee, Kwan Seop; Lee, Hyun; Sohn, Jeong Hee; Kim, Sam Soo

    2009-01-01

    To evaluate the distribution of color flow signals on color Doppler ultrasonography of vascular leiomyomas and to correlate them with pathologic findings. We retrospectively analyzed color Doppler ultrasonographic images and pathologic slides of six vascular leiomyomas. We classified the patterns of distribution of color flow signals into localized compact cluster types and non-cluster types, and the pathologic findings into three subtypes: solid, venous and cavernous. All cases showed well-defined homogenous hypoechoic subcutaneous masses on gray-scale ultrasonography. Three cases showed localized compact cluster types on color Doppler ultrasonography, one in each subtype (solid, venous and cavernous). For the three non-cluster types, again there was on in each subtype. In addition, on pathologic analysis the zone of the localized compact cluster of color flow signals coincided with a cluster of larger, vascular caliber masses. Localized compact clusters of color flow signals on color Doppler ultrasonography were seen in 50% of our cases and correlated with a cluster of larger vascular caliber in the mass. But the pattern of distribution of color flows didn't show a correlation with pathologic type

  6. The vascular basement membrane in the healthy and pathological brain.

    Science.gov (United States)

    Thomsen, Maj S; Routhe, Lisa J; Moos, Torben

    2017-10-01

    The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes. Major changes in the molecular composition of the vascular basement membrane are observed in acute and chronic neuropathological settings. In the present review, we cover the significance of the vascular basement membrane in the healthy and pathological brain. In stroke, loss of BBB integrity is accompanied by upregulation of proteolytic enzymes and degradation of vascular basement membrane proteins. There is yet no causal relationship between expression or activity of matrix proteases and the degradation of vascular matrix proteins in vivo. In Alzheimer's disease, changes in the vascular basement membrane include accumulation of Aβ, composite changes, and thickening. The physical properties of the vascular basement membrane carry the potential of obstructing drug delivery to the brain, e.g. thickening of the basement membrane can affect drug delivery to the brain, especially the delivery of nanoparticles.

  7. Circulating elastin peptides, role in vascular pathology.

    Science.gov (United States)

    Robert, L; Labat-Robert, J

    2014-12-01

    The atherosclerotic process starts with the degradation of elastic fibers. Their presence was demonstrated in the circulation as well as several of their biological properties elucidated. We described years ago a procedure to obtain large elastin peptides by organo-alkaline hydrolysis, κ-elastin. This method enabled also the preparation of specific antibodies used to determine elastin peptides, as well as anti-elastin antibodies in body fluids and tissue extracts. Elastin peptides were determined in a large number of human blood samples. Studies were carried out to explore their pharmacological properties. Similar recent studies by other laboratories confirmed our findings and arose new interest in circulating elastin peptides for their biological activities. This recent trend justified the publication of a review of the biological and pathological activities of elastin peptides demonstrated during our previous studies, subject of this article. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype

    International Nuclear Information System (INIS)

    Nagy, Janice A.; Senger, Donald R.

    2006-01-01

    Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype

  9. Malignant vascular lesions of bone: radiologic and pathologic features

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    Wenger, D.E. [Dept. of Diagnostic Radiology, Mayo Foundation, Rochester, MN (United States); Wold, L.E. [Dept. of Laboratory Medicine and Pathology, Mayo Foundation, Rochester, MN (United States)

    2000-11-01

    The malignant vascular tumors of bone represent an uncommon diverse group of tumors with widely variable clinical and radiographic presentations. Although the radiographic imaging features of the lytic osseous lesions typically seen with this group of tumors are relatively nonspecific, the propensity to develop multifocal disease in an anatomic region is a feature that can be helpful in suggesting the diagnosis of a vascular tumor. The differential diagnosis varies according to the age of the patient and presence of solitary or multifocal disease. The histologic features are variable and range from tumors with vasoformative features to those that mimic mesenchymal neoplasm or metastatic carcinoma. Familiarity with the radiographic and pathologic spectrum of disease is essential for making an accurate diagnosis in this diverse group of neoplasms. This paper will provide a review of the nomenclature for the malignant vascular tumors of bone and discuss the radiographic and pathologic differential diagnosis. (orig.)

  10. Vascular pathology: Cause or effect in Alzheimer disease?

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    Rius-Pérez, S; Tormos, A M; Pérez, S; Taléns-Visconti, R

    2018-03-01

    Alzheimer disease (AD) is the main cortical neurodegenerative disease. The incidence of this disease increases with age, causing significant medical, social and economic problems, especially in countries with ageing populations. This review aims to highlight existing evidence of how vascular dysfunction may contribute to cognitive impairment in AD, as well as the therapeutic possibilities that might arise from this evidence. The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. The link between neurodegeneration and vascular dysfunction pathways has provided new drug targets and therapeutic approaches that will add to the treatments for AD. It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Vascular Endothelial Growth Factor from Embryonic Status to Cardiovascular Pathology

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    Mohsen Azimi-Nezhad

    2014-05-01

    Full Text Available Vascular endothelial growth factor (VEGF is a multifunctional cytokine with distinct functions in angiogenesis, lymphangiogenesis, vascular permeability, and hematopoiesis. VEGF is a highly conserved, disulfide-bonded dimeric glycoprotein of 34 to 45 kDa produced by several cell types including fibroblasts, neutrophils, endothelial cells, and peripheral blood mononuclear cells, particularly T lymphocytes and macrophages. Six VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene, consisting of 121, 145, 165, 183, 189, or 206 amino acids. VEGF121, VEGF145, and VEGF165 are secreted whereas VEGF183, VEGF189, and VEGF206 are cell membrane-bound. VEGF145 has a key role during the vascularization of the human ovarian follicle and corpus luteum, in the placentation and embryonic periods, and in bone and wound healing, while VEGF165 is the most abundant and biologically active isoform. VEGF has been linked with a number of vascular pathologies including cardiovascular diseases such ischemic heart disease, heart failure, stroke, and diabetes and its related complications. In this review we aimed to present some important roles of VEGF in a number of clinical issues and indicate its involvement in several phenomena from the initial steps of the embryonic period to cardiovascular diseases.

  12. Benign vascular lesions of bone: radiologic and pathologic features

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    Wenger, D.E.; Wold, L.E. [Mayo Foundation, Rochester, MN (United States)

    2000-02-01

    The benign vascular tumors of bone represent a diverse group of tumors that can present with a broad spectrum of clinical signs and symptoms. They can also present a significant diagnostic challenge due to their widely variable radiographic imaging and histologic features. Some of the tumors manifest as clearly benign lesions with tissue-specific diagnostic imaging features, while others have non-specific imaging features that may simulate malignant neoplasm. This article will provide a review of the nomenclature and the characteristic radiographic and pathologic features of the benign vascular lesions of bone. The information will aid in improving our diagnostic accuracy and enhance our understanding of the biologic potential of this diverse group of osseous lesions. (orig.)

  13. Benign vascular lesions of bone: radiologic and pathologic features

    International Nuclear Information System (INIS)

    Wenger, D.E.; Wold, L.E.

    2000-01-01

    The benign vascular tumors of bone represent a diverse group of tumors that can present with a broad spectrum of clinical signs and symptoms. They can also present a significant diagnostic challenge due to their widely variable radiographic imaging and histologic features. Some of the tumors manifest as clearly benign lesions with tissue-specific diagnostic imaging features, while others have non-specific imaging features that may simulate malignant neoplasm. This article will provide a review of the nomenclature and the characteristic radiographic and pathologic features of the benign vascular lesions of bone. The information will aid in improving our diagnostic accuracy and enhance our understanding of the biologic potential of this diverse group of osseous lesions. (orig.)

  14. Clinical-pathologic correlations in vascular cognitive impairment and dementia.

    Science.gov (United States)

    Flanagan, Margaret; Larson, Eric B; Latimer, Caitlin S; Cholerton, Brenna; Crane, Paul K; Montine, Kathleen S; White, Lon R; Keene, C Dirk; Montine, Thomas J

    2016-05-01

    The most common causes of cognitive impairment and dementia are Alzheimer's disease (AD) and vascular brain injury (VBI), either independently, in combination, or in conjunction with other neurodegenerative disorders. The contribution of VBI to cognitive impairment and dementia, particularly in the context of AD pathology, has been examined extensively yet remains difficult to characterize due to conflicting results. Describing the relative contribution and mechanisms of VBI in dementia is important because of the profound impact of dementia on individuals, caregivers, families, and society, particularly the stability of health care systems with the rapidly increasing age of our population. Here we discuss relationships between pathologic processes of VBI and clinical expression of dementia, specific subtypes of VBI including microvascular brain injury, and what is currently known regarding contributions of VBI to the development and pathogenesis of the dementia syndrome. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. High wall shear stress and spatial gradients in vascular pathology: a review.

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    Dolan, Jennifer M; Kolega, John; Meng, Hui

    2013-07-01

    Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.

  16. Vascular endothelial growth factor (VEGF and prostate pathology

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    Francisco Botelho

    2010-08-01

    Full Text Available PURPOSE: Previous studies suggest that vascular endothelial growth factor (VEGF circulating levels might improve identification of patients with prostate cancer but results are conflicting. Our aim was to compare serum VEGF levels across different prostate pathologies (including benign prostatic hyperplasia, prostatitis, high grade prostate intraepithelial neoplasia and prostate cancer in patients at high risk of prostate cancer. MATERIALS AND METHODS: We consecutively enrolled 186 subjects with abnormal digital rectal examination and/or total PSA (tPSA = 2.5 ng/mL. Blood was collected before diagnostic ultrasound guided trans-rectal prostate biopsy, or any prostate oncology treatment, to measure PSA isoforms and VEGF. Unconditional logistic regression was used to compute age-, tPSA- and free/total PSA-adjusted odds ratios (OR and respective 95% confidence intervals (95% CI for the association between serum VEGF and different prostatic pathologies. RESULTS: Prostate biopsy main diagnoses were normal or benign prostatic hyperplasia (27.3%, prostatitis (16.6%, and prostatic cancer (55.0%. The median VEGF levels (ng/mL in these groups were 178.2, 261.3 and 266.4 (p = 0.029, respectively, but no significant differences were observed for benign vs. malignant pathologies (215.2 vs. 266.4, p = 0.551. No independent association was observed between VEGF (3rd vs. 1st third and prostate cancer, when compared to benign conditions (adjusted OR = 1.44; CI 95%: 0.64-3.26. CONCLUSIONS: In patients at high risk of prostate cancer, circulating VEGF levels have no clinical role in deciding which patients should be submitted to prostate biopsy. Prostatitis patients, often with higher PSA levels, also present high serum levels of VEGF, and their inclusion in control groups might explain the heterogeneous results in previous studies.

  17. Biophysical Regulation of Vascular Differentiation and Assembly

    CERN Document Server

    Gerecht, Sharon

    2011-01-01

    The ability to grow stem cells in the laboratory and to guide their maturation to functional cells allows us to study the underlying mechanisms that govern vasculature differentiation and assembly in health and disease. Accumulating evidence suggests that early stages of vascular growth are exquisitely tuned by biophysical cues from the microenvironment, yet the scientific understanding of such cellular environments is still in its infancy. Comprehending these processes sufficiently to manipulate them would pave the way to controlling blood vessel growth in therapeutic applications. This book assembles the works and views of experts from various disciplines to provide a unique perspective on how different aspects of its microenvironment regulate the differentiation and assembly of the vasculature. In particular, it describes recent efforts to exploit modern engineering techniques to study and manipulate various biophysical cues. Biophysical Regulation of Vascular Differentiation and Assembly provides an inter...

  18. Genetic Regulation of Vascular Development: Building the Zebrafish Vascular Tree

    NARCIS (Netherlands)

    R.L.J.M. Herpers (Robert)

    2010-01-01

    textabstractThe extensive networks of blood and lymphatic vessels within the vertebrate body are essential for the transport and delivery of fluids, gases, macromolecules and cells, and play important roles in facilitating immune responses. The development of the vascular tree requires a highly

  19. Intramuscular vascular malformations of an extremity: findings on MR imaging and pathologic correlation

    International Nuclear Information System (INIS)

    Kim, E.Y.; Ahn, J.M.; Yoon, H.K.; Do, Y.S.; Kim, S.H.; Choo, S.W.; Choo, I.W.; Suh, Y.L.; Kim, S.M.; Kang, H.S.

    1999-01-01

    Objective. To analyze the findings of intramuscular vascular malformations of an extremity on MR imaging and to correlate these findings with histopathologic examination.Design and patients. The findings on MR imaging and the medical records of 14 patients with an intramuscular vascular malformation of the extremity were retrospectively studied. All patients underwent surgical excision. Diagnoses were based on the results of pathologic examination. Findings on MR imaging were noted and correlated with the histopathologic findings.Results. Intramuscular vascular malformations of an extremity showed multi-septate, honeycomb, or mixed appearance on MR imaging. Multi-septate areas correlated with dilated and communicating vascular spaces with flattened endothelium. Honeycomb areas corresponded to vascular spaces with inconspicuous small lumina and thickened vascular walls. Areas of increased signal intensity on T2-weighted images were found in all intramuscular vascular malformations. Infiltrative margins were more commonly seen in intramuscular lymphaticovenous malformations. Adherence to neurovascular structures and orientation of the lesion along the long axis of the affected muscle were more commonly seen in intramuscular venous malformations.Conclusions. Intramuscular vascular malformations showed either a multi-septate, honeycomb, or mixed appearance, reflecting the size of the vascular spaces and the thickness of the smooth muscles of the vessel walls. Prediction of the subtype of an intramuscular vascular malformation of an extremity on MR imaging seems to be difficult, although there are associated findings that may be helpful in the differential diagnosis of each subtype. (orig.)

  20. Regulation of Hyaluronan Synthesis in Vascular Diseases and Diabetes

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    Paola Moretto

    2015-01-01

    Full Text Available Cell microenvironment has a critical role determining cell fate and modulating cell responses to injuries. Hyaluronan (HA is a ubiquitous extracellular matrix glycosaminoglycan that can be considered a signaling molecule. In fact, interacting with several cell surface receptors can deeply shape cell behavior. In vascular biology, HA triggers smooth muscle cells (SMCs dedifferentiation which contributes to vessel wall thickening. Furthermore, HA is able to modulate inflammation by altering the adhesive properties of endothelial cells. In hyperglycemic conditions, HA accumulates in vessels and can contribute to the diabetic complications at micro- and macrovasculature. Due to the pivotal role in favoring atherogenesis and neointima formation after injuries, HA could be a new target for cardiovascular pathologies. This review will focus on the recent findings regarding the regulation of HA synthesis in human vascular SMCs. In particular, the effects of the intracellular HA substrates availability, adenosine monophosphate-activated protein kinase (AMPK, and protein O-GlcNAcylation on the main HA synthetic enzyme (i.e., HAS2 will be discussed.

  1. Matrix Metalloproteinases: Inflammatory Regulators of Cell Behaviors in Vascular Formation and Remodeling

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    Qishan Chen

    2013-01-01

    Full Text Available Abnormal angiogenesis and vascular remodeling contribute to pathogenesis of a number of disorders such as tumor, arthritis, atherosclerosis, restenosis, hypertension, and neurodegeneration. During angiogenesis and vascular remodeling, behaviors of stem/progenitor cells, endothelial cells (ECs, and vascular smooth muscle cells (VSMCs and its interaction with extracellular matrix (ECM play a critical role in the processes. Matrix metalloproteinases (MMPs, well-known inflammatory mediators are a family of zinc-dependent proteolytic enzymes that degrade various components of ECM and non-ECM molecules mediating tissue remodeling in both physiological and pathological processes. MMPs including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MT1-MMP, are stimulated and activated by various stimuli in vascular tissues. Once activated, MMPs degrade ECM proteins or other related signal molecules to promote recruitment of stem/progenitor cells and facilitate migration and invasion of ECs and VSMCs. Moreover, vascular cell proliferation and apoptosis can also be regulated by MMPs via proteolytically cleaving and modulating bioactive molecules and relevant signaling pathways. Regarding the importance of vascular cells in abnormal angiogenesis and vascular remodeling, regulation of vascular cell behaviors through modulating expression and activation of MMPs shows therapeutic potential.

  2. Endothelin-1 Regulation of exercise-induced changes in flow: Dynamic regulation of vascular tone

    NARCIS (Netherlands)

    Rapoport, R.M. (Robert M.); D. Merkus (Daphne)

    2017-01-01

    textabstractAlthough endothelin (ET)-1 is a highly potent vasoconstrictor with considerable efficacy in numerous vascular beds, the role of endogenous ET-1 in the regulation of vascular tone remains unclear. The perspective that ET-1 plays little role in the on-going regulation of vascular tone at

  3. 3D Modeling of Vascular Pathologies from contrast enhanced magnetic resonance images (MRI)

    International Nuclear Information System (INIS)

    Cantor Rivera, Diego; Orkisz, Maciej; Arias, Julian; Uriza, Luis Felipe

    2007-01-01

    This paper presents a method for generating 3D vascular models from contrast enhanced magnetic resonance images (MRI) using a fast marching algorithm. The main contributions of this work are: the use of the original image for defining a speed function (which determines the movement of the interface) and the calculation of the time in which the interface identifies the artery. The proposed method was validated on pathologic carotid artery images of patients and vascular phantoms. A visual appraisal of vascular models obtained with the method shows a satisfactory extraction of the vascular wall. A quantitative assessment proved that the generated models depend on the values of algorithm parameters. The maximum induced error was equal to 1.34 voxels in the diameter of the measured stenoses.

  4. Risk of incident clinical diagnosis of AD-type dementia attributable to pathology-confirmed vascular disease

    Science.gov (United States)

    Dodge, Hiroko H.; Zhu, Jian; Woltjer, Randy; Nelson, Peter T.; Bennett, David A.; Cairns, Nigel J.; Fardo, David W.; Kaye, Jeffrey A.; Lyons, Deniz-Erten; Mattek, Nora; Schneider, Julie A; Silbert, Lisa C.; Xiong, Chengjie; Yu, Lei; Schmitt, Frederick A.; Kryscio, Richard J.; Abner, Erin L.

    2016-01-01

    Introduction Presence of cerebrovascular pathology may increase the risk of clinical diagnosis of AD. Methods We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modelling of Aging and Risk of Transition (SMART) study, a consortium of longitudinal cohort studies with over 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). Results The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. Discussion Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required. PMID:28017827

  5. Placental vascular pathology and increased thrombin generation as mechanisms of disease in obstetrical syndromes

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    Salvatore Andrea Mastrolia

    2014-11-01

    Full Text Available Obstetrical complications including preeclampsia, fetal growth restriction, preterm labor, preterm prelabor rupture of membranes and fetal demise are all the clinical endpoint of several underlying mechanisms (i.e., infection, inflammation, thrombosis, endocrine disorder, immunologic rejection, genetic, and environmental, therefore, they may be regarded as syndromes. Placental vascular pathology and increased thrombin generation were reported in all of these obstetrical syndromes. Moreover, elevated concentrations of thrombin-anti thrombin III complexes and changes in the coagulation as well as anticoagulation factors can be detected in the maternal circulation prior to the clinical development of the disease in some of these syndromes. In this review, we will assess the changes in the hemostatic system during normal and complicated pregnancy in maternal blood, maternal–fetal interface and amniotic fluid, and describe the contribution of thrombosis and vascular pathology to the development of the great obstetrical syndromes.

  6. Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology.

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    Shaomei Wang

    Full Text Available BACKGROUND: Retinitis pigmentosa (RP is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS rat, a well-established animal model for RP. METHODOLOGY/PRINCIPAL FINDINGS: Animals received syngeneic MSCs (1x10(6 cells by tail vein at an age before major photoreceptor loss. PRINCIPAL RESULTS: both rod and cone photoreceptors were preserved (5-6 cells thick at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs. CONCLUSIONS/SIGNIFICANCE: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort

  7. The adventitia: essential regulator of vascular wall structure and function.

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    Stenmark, Kurt R; Yeager, Michael E; El Kasmi, Karim C; Nozik-Grayck, Eva; Gerasimovskaya, Evgenia V; Li, Min; Riddle, Suzette R; Frid, Maria G

    2013-01-01

    The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is composed of a variety of cells, including fibroblasts, immunomodulatory cells (dendritic cells and macrophages), progenitor cells, vasa vasorum endothelial cells and pericytes, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to influence the tone and structure of the vessel wall; to initiate and perpetuate chronic vascular inflammation; and to stimulate expansion of the vasa vasorum, which can act as a conduit for continued inflammatory and progenitor cell delivery to the vessel wall. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in.

  8. Critical Endothelial Regulation by LRP5 during Retinal Vascular Development

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    Huang, Wei; Li, Qing; Amiry-Moghaddam, Mahmood; Hokama, Madoka; Sardi, Sylvia H.; Nagao, Masashi; Warman, Matthew L.; Olsen, Bjorn R.

    2016-01-01

    Vascular abnormalities in the eye are the leading cause of many forms of inherited and acquired human blindness. Loss-of-function mutations in the Wnt-binding co-receptor LRP5 leads to aberrant ocular vascularization and loss of vision in genetic disorders such as osteoporosis-pseudoglioma syndrome. The canonical Wnt-β-catenin pathway is known to regulate retinal vascular development. However, it is unclear what precise role LPR5 plays in this process. Here, we show that loss of LRP5 function in mice causes retinal hypovascularization during development as well as retinal neovascularization in adulthood with disorganized and leaky vessels. Using a highly specific Flk1-CreBreier line for vascular endothelial cells, together with several genetic models, we demonstrate that loss of endothelium-derived LRP5 recapitulates the retinal vascular defects in Lrp5-/- mice. In addition, restoring LRP5 function only in endothelial cells in Lrp5-/- mice rescues their retinal vascular abnormalities. Furthermore, we show that retinal vascularization is regulated by LRP5 in a dosage dependent manner and does not depend on LRP6. Our study provides the first direct evidence that endothelium-derived LRP5 is both necessary and sufficient to mediate its critical role in the development and maintenance of retinal vasculature. PMID:27031698

  9. Vascular Pathology in the Extracranial Vertebral Arteries in Patients with Acute Ischemic Stroke

    DEFF Research Database (Denmark)

    Bentsen, L; Nygård, A; Ovesen, C

    2014-01-01

    INTRODUCTION: Vascular pathology in the extracranial vertebral arteries remains among the possible causes in cryptogenic stroke. However, the diagnosis is challenged by the great variety in the anatomy of the vertebral arteries, clinical symptoms and difficulties in the radiological assessments....... The aim of this study was to assess the prevalence of CT angiography (CTA)-detected pathological findings in the extracranial vertebral arteries in an acute stroke population and secondly to determine the frequency of posterior pathology as probable cause in patients with otherwise cryptogenic stroke....... METHOD: The analysis was based on 657 consecutive patients with symptoms of acute stroke and a final diagnosis of ischemic stroke or transient ischemic attack. On admission, a noncontrast CT cerebrum and CTA were performed. A senior consultant neuroradiologist, blinded to clinical data, reviewed all CTA...

  10. Role of vascular potassium channels in the regulation of renal hemodynamics

    DEFF Research Database (Denmark)

    Sørensen, Charlotte Mehlin; Braunstein, Thomas Hartig; von Holstein-Rathlou, Niels-Henrik

    2012-01-01

    of one or more classes of K+ channels will lead to a change in hemodynamic resistance and therefore of renal blood flow and glomerular filtration pressure. Through these effects, the activity of renal vascular K+ channels influences renal salt and water excretion, fluid homeostasis, and ultimately blood...... pressure. Four main classes of K+ channels [calcium activated (KCa), inward rectifier (Kir), voltage activated (KV), and ATP sensitive (KATP)] are found in the renal vasculature. Several in vitro experiments have suggested a role for individual classes of K+ channels in the regulation of renal vascular...... function. Results from in vivo experiments are sparse. We discuss the role of the different classes of renal vascular K+ channels and their possible role in the integrated function of the renal microvasculature. Since several pathological conditions, among them hypertension, are associated with alterations...

  11. Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model.

    Science.gov (United States)

    Shen, Weiyong; Fruttiger, Marcus; Zhu, Ling; Chung, Sook H; Barnett, Nigel L; Kirk, Joshua K; Lee, SoRa; Coorey, Nathan J; Killingsworth, Murray; Sherman, Larry S; Gillies, Mark C

    2012-11-07

    Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuroprotective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.

  12. Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment.

    Science.gov (United States)

    Skrobot, Olivia A; Attems, Johannes; Esiri, Margaret; Hortobágyi, Tibor; Ironside, James W; Kalaria, Rajesh N; King, Andrew; Lammie, George A; Mann, David; Neal, James; Ben-Shlomo, Yoav; Kehoe, Patrick G; Love, Seth

    2016-11-01

    There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet's AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate

  13. Longitudinal Effects of Metabolic Syndrome on Alzheimer and Vascular Related Brain Pathology

    Directory of Open Access Journals (Sweden)

    Feng Lin

    2014-06-01

    Full Text Available Background/Aims: This study examines the longitudinal effect of metabolic syndrome (MetS on brain-aging indices among cognitively normal (CN and amnestic mild cognitive impairment (aMCI groups [single-domain aMCI (saMCI and multiple-domain aMCI (maMCI]. Methods: The study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238 from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD biomarkers, namely [18F]fluorodeoxyglucose (FDG-positron emission tomography (PET regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM volume, was examined as a comparison. Results: The vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups. Conclusion: At the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology.

  14. Regulation and Roles of Urocortins in the Vascular System

    Directory of Open Access Journals (Sweden)

    Kazunori Kageyama

    2012-01-01

    Full Text Available Urocortins (Ucns are members of the corticotropin-releasing factor (CRF family of peptides. Ucns would have potent effects on the cardiovascular system via the CRF receptor type 2 (CRF2 receptor. Regulation and roles of each Ucn have been determined in the vascular system. Ucns have more potent vasodilatory effects than CRF. Human umbilical vein endothelial cells (HUVECs express Ucns1-3 mRNAs, and the receptor, CRF2a receptor mRNA. Ucns1-3 mRNA levels are differentially regulated in HUVECs. Differential regulation of Ucns may suggest differential roles of those in HUVECs. Ucn1 and Ucn2 have strong effects on interleukin (IL-6 gene expression and secretion in rat aortic smooth muscle A7r5 cells. The increase that we observed in IL-6 levels following Ucn treatment of A7r5 cells suggests that smooth muscle cells may be a source of IL-6 secretion under physiological stress conditions. Ucns are important and unique modulators of vascular smooth muscle cells and act directly or indirectly as autocrine and paracrine factors in the vascular system.

  15. Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus.

    Science.gov (United States)

    Yahagi, Kazuyuki; Kolodgie, Frank D; Lutter, Christoph; Mori, Hiroyoshi; Romero, Maria E; Finn, Aloke V; Virmani, Renu

    2017-02-01

    The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification. © 2016 American Heart Association, Inc.

  16. Hemifacial Pain and Hemisensory Disturbance Referred from Occipital Neuralgia Caused by Pathological Vascular Contact of the Greater Occipital Nerve

    OpenAIRE

    Son, Byung-chul; Choi, Jin-gyu

    2017-01-01

    Here we report a unique case of chronic occipital neuralgia caused by pathological vascular contact of the left greater occipital nerve. After 12 months of left-sided, unremitting occipital neuralgia, a hypesthesia and facial pain developed in the left hemiface. The decompression of the left greater occipital nerve from pathological contacts with the occipital artery resulted in immediate relief for hemifacial sensory change and facial pain, as well as chronic occipital neuralgia. Although re...

  17. Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.

    Science.gov (United States)

    Findeisen, Hannes M; Kahles, Florian K; Bruemmer, Dennis

    2013-04-01

    Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.

  18. Pathological interstitial vascular proliferation adjacent to glomeruli in immunoglobulin a nephropathy

    Directory of Open Access Journals (Sweden)

    Honami Mori

    2016-01-01

    Full Text Available We detected an increase in small arterioles around glomeruli, particularly adjacent to tuft adhesive lesions in immunoglobulin A nephropathy (IgAN, for the 1 st time, as far as we know. We labeled these as periglomerular microarterioles (PGMAs. This study aimed to clarify the pathological significance of PGMAs. Sixty-two patients with IgAN and 19 controls with minor glomerular abnormalities without proteinuria were evaluated in this study. The number of PGMAs located between the Bowman′s capsule and the adjoining tubules was counted for each glomerulus. The mean number of PGMAs per glomerulus in cases of IgAN was significantly higher than those of the controls (0.530 ± 0.477 vs. 0.240 ± 0.182, P <0.05. Serial sections showed that most of the PGMAs were in contact with adjacent glomeruli (71.8%, through tuft adhesive lesions (52.1%, or the vascular pole (19.7%. By single regression analysis, the number of PGMAs was found to be positively correlated with the incidence of glomerular tuft adhesion, glomerular sclerosis, or the area of interstitial fibrosis in IgAN. By multiple regression analysis, the incidence of glomerular tuft adhesion was found to be the only independent pathological feature to correlate with the number of PGMAs (P = 0.0006. We have noticed the existence of PGMAs around glomeruli as a pathological finding of IgAN. Furthermore, the number of PGMAs was associated with the incidence of tuft adhesive lesion in glomeruli of IgAN although there was no relationship between the presence of PGMAs and clinical parameters including urinary protein excretion or creatinine clearance in the present study.

  19. Regulation of Nox enzymes expression in vascular pathophysiology: Focusing on transcription factors and epigenetic mechanisms

    Directory of Open Access Journals (Sweden)

    Simona-Adriana Manea

    2015-08-01

    Full Text Available NADPH oxidases (Nox represent a family of hetero-oligomeric enzymes whose exclusive biological function is the generation of reactive oxygen species (ROS. Nox-derived ROS are essential modulators of signal transduction pathways that control key physiological activities such as cell growth, proliferation, migration, differentiation, and apoptosis, immune responses, and biochemical pathways. Enhanced formation of Nox-derived ROS, which is generally associated with the up-regulation of different Nox subtypes, has been established in various pathologies, namely cardiovascular diseases, diabetes, obesity, cancer, and neurodegeneration. The detrimental effects of Nox-derived ROS are related to alterations in cell signalling and/or direct irreversible oxidative damage of nucleic acids, proteins, carbohydrates, and lipids. Thus, understanding of transcriptional regulation mechanisms of Nox enzymes have been extensively investigated in an attempt to find ways to counteract the excessive formation of Nox-derived ROS in various pathological states. Despite the numerous existing data, the molecular pathways responsible for Nox up-regulation are not completely understood. This review article summarizes some of the recent advances and concepts related to the regulation of Nox expression in the vascular pathophysiology. It highlights the role of transcription factors and epigenetic mechanisms in this process. Identification of the signalling molecules involved in Nox up-regulation, which is associated with the onset and development of cardiovascular dysfunction may contribute to the development of novel strategies for the treatment of cardiovascular diseases.

  20. Endothelin-1 Regulation of Exercise-Induced Changes in Flow: Dynamic Regulation of Vascular Tone

    Directory of Open Access Journals (Sweden)

    Robert M. Rapoport

    2017-10-01

    Full Text Available Although endothelin (ET-1 is a highly potent vasoconstrictor with considerable efficacy in numerous vascular beds, the role of endogenous ET-1 in the regulation of vascular tone remains unclear. The perspective that ET-1 plays little role in the on-going regulation of vascular tone at least under physiologic conditions is supported by findings that potential ET-1 constriction is minimized by the release of the vasodilator and ET-1 synthesis inhibitor, nitric oxide (NO. Indeed, ET-1 release and constriction is self-limited by ET-1-induced, endothelial ETB receptor-mediated release of NO. Moreover, even if the balance between ET-1 and NO were reversed as the result of lowered NO activity, as occurs in a number of pathophysiologies associated with endothelial dysfunction, the well-known resistance of ET-1 constriction to reversal (as determined with exogenous ET-1 precludes ET-1 in the dynamic, i.e., moment-to-moment, regulation of vascular tone. On the other hand, and as presently reviewed, findings of ET-1-dependent modulation of organ blood flow with exercise under physiologic conditions demonstrate the dynamic regulation of vascular tone by ET-1. We speculate that this regulation is mediated at least in part through changes in ET-1 synthesis/release caused by pulsatile flow-induced shear stress and NO.

  1. Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.

    Science.gov (United States)

    Ishii, Makoto; Iadecola, Costantino

    2016-05-01

    Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Regulation of tyrosine phosphatases in the adventitia during vascular remodelling

    International Nuclear Information System (INIS)

    Micke, Patrick; Hackbusch, Daniel; Mercan, Sibel; Stawowy, Philipp; Tsuprykov, Oleg; Unger, Thomas; Ostman, Arne; Kappert, Kai

    2009-01-01

    Protein tyrosine phosphatases (PTPs) are regulators of growth factor signalling in vascular remodelling. The aim of this study was to evaluate PTP expression in the context of PDGF-signalling in the adventitia after angioplasty. Utilising a rat carotid artery model, the adventitial layers of injured and non-injured vessels were laser microdissected. The mRNA expression of the PDGF β-receptor, the ligands PDGF-A/B/C/D and the receptor-antagonising PTPs (DEP-1, TC-PTP, SHP-2, PTP1B) were determined and correlated to vascular morphometrics, proliferation markers and PDGF β-receptor phosphorylation. The levels of the PDGF β-receptor, PDGF-C and PDGF-D were upregulated concurrently with the antagonising PTPs DEP-1 and TC-PTP at day 8, and normalised at day 14 after vessel injury. Although the proliferation parameters were time-dependently altered in the adventitial layer, the phosphorylation of the PDGF β-receptor remained unchanged. The expression dynamics of specific PTPs indicate a regulatory role of PDGF-signalling also in the adventitia during vascular remodelling.

  3. Regulation of cyclooxygenase expression in cultured vascular cells

    International Nuclear Information System (INIS)

    Pash, J.M.

    1988-01-01

    Arachidonic acid metabolism in vascular tissue results in synthesis of prostacylin. The key enzyme in this synthesis pathway, cyclooxygenase, is down-regulated through self-inactivation. An analogous refractory state is produced by aspirin which irreversibly acetylates the enzyme. To further understand this phenomenon, the inactivation and recovery of cyclooxygenase activity was assayed in cultured ray vascular smooth muscle cells using exogenously added arachidonic acid. Self-inactivation of cyclooxygenase was observed following treatment with micromolar amounts of arachidonic acid. The recovery of cyclooxygenase activity following self-inactivation was analogous to that observed following aspirin-inactivation in that it depended on protein synthesis and required either serum or EGF. Two additional factors, TGF-β and uric acid, were found to enhance the stimulation of cyclooxygenase recovery by EGF. A defined medium containing 10 ng/mL EGF, 1 ng/mL TGFβ and 0.1 mM uric acid duplicated the cyclooxygenase recovery activity of 10% serum. Stimulation of cyclooxygenase activity by EGF and TGF-β was inhibited by cycloheximide but not by actinomycin-D, indicating a link to increased translation of pre-existing mRNA. A lack of significant effect on overall protein synthesis by EGF and TGF-β, measured by [ 35 S]-methionine incorporation under conditions where a multi-fold increase in cyclooxygenase activity was seen, indicates that the translational regulation of a small fraction of total mRNA and possibly cyclooxygenase is occurring

  4. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.

    Science.gov (United States)

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M; Kirkby, Nicholas S; van de Putte, Elisabeth E Fransen; Christen, Sibylle; Kimmitt, Robert A; Moorhouse, Rebecca; Castellan, Raphael F P; Kotelevtsev, Yuri V; Kuc, Rhoda E; Davenport, Anthony P; Dhaun, Neeraj; Webb, David J; Hadoke, Patrick W F

    2017-02-01

    The role of smooth muscle endothelin B (ET B ) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET B receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET B receptors were selectively deleted from smooth muscle by crossing floxed ET B mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET B deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET B was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET B -mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET B -mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET B knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ET B blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET B -mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET B knockout mice. In the absence of other pathology, ET B receptors in vascular smooth muscle make a small but significant contribution to ET B -dependent regulation of BP. These ET B receptors have no effect on vascular contraction or neointimal remodeling. © 2016 The Authors.

  5. Cutaneous vascular anomalies associated with neural tube defects: nomenclature and pathology revisited.

    Science.gov (United States)

    Maugans, Todd; Sheridan, Rachel M; Adams, Denise; Gupta, Anita

    2011-07-01

    Lumbosacral cutaneous vascular anomalies associated with neural tube defects are frequently described in the literature as "hemangiomas." The classification system for pediatric vascular anomalies developed by the International Society for the Study of Vascular Anomalies provides a framework to accurately diagnose these lesions. To apply this classification to vascular cutaneous anomalies overlying myelodysplasias. A retrospective analysis of patients with neural tube defects and lumbosacral cutaneous vascular lesions was performed. All eligible patients had detailed histopathologic analysis of skin and spinal cord/placode lesions. Clinical and radiologic features were analyzed. Conventional histology and GLUT-1 immunostaining were performed to differentiate infantile capillary hemangiomas from capillary vascular malformations. Ten cases with cutaneous lesions associated with neural tube defects were reviewed. Five lesions were diagnosed as infantile capillary hemangiomas based upon histology and positive GLUT-1 endothelial reactivity. These lesions had a strong association with dermal sinus tracts. No reoperations were required for residual intraspinal vascular lesions, and overlying cutaneous vascular anomalies involuted with time. The remaining 5 lesions were diagnosed as capillary malformations. These occurred with both open and closed neural tube defects, did not involute, and demonstrated enlargement and darkening due to vascular congestion. The International Society for the Study of Vascular Anomalies scheme should be used to describe the cutaneous vascular lesions associated with neural tube defects: infantile capillary hemangiomas and capillary malformations. We advocate that these lesions be described as "vascular anomalies" or "stains" pending accurate diagnosis by clinical, histological, and immunohistochemical evaluations.

  6. Endothelium-derived fibronectin regulates neonatal vascular morphogenesis in an autocrine fashion.

    Science.gov (United States)

    Turner, Christopher J; Badu-Nkansah, Kwabena; Hynes, Richard O

    2017-11-01

    Fibronectin containing alternatively spliced EIIIA and EIIIB domains is largely absent from mature quiescent vessels in adults, but is highly expressed around blood vessels during developmental and pathological angiogenesis. The precise functions of fibronectin and its splice variants during developmental angiogenesis however remain unclear due to the presence of cardiac, somitic, mesodermal and neural defects in existing global fibronectin KO mouse models. Using a rare family of surviving EIIIA EIIIB double KO mice, as well as inducible endothelial-specific fibronectin-deficient mutant mice, we show that vascular development in the neonatal retina is regulated in an autocrine manner by endothelium-derived fibronectin, and requires both EIIIA and EIIIB domains and the RGD-binding α5 and αv integrins for its function. Exogenous sources of fibronectin do not fully substitute for the autocrine function of endothelial fibronectin, demonstrating that fibronectins from different sources contribute differentially to specific aspects of angiogenesis.

  7. CT features on increased cerebral vascular density and its pathological mechanism in patients with cyanotic congenital disease

    International Nuclear Information System (INIS)

    Liu Hui; Zhang Xintang; Wang Jin; Tian Min; He Yuping; Zhao Jinqi; He Qian; Chen Huanjun; Li Fawei

    2012-01-01

    Objective: To investigate CT features on increased cerebral vascular density and its pathological mechanism in patients with cyanotic congenital heart disease (CCHD). Methods: Preoperative brain CT scan and clinical data in 82 patients suffering from CCHD were analyzed. According to the increased levels of vascular density, patients were divided into 4 groups: normal, mild, moderate and severe. Relationships between the increased levels of vascular density and Hb, RBC, HCT, as well as the degree of cyanosis,were studied. AVONA was carried out to test blood CT value of cerebral sinuses, Hb, RBC and HCT in different groups. Descriptive analysis and linear regression were adopted to study the correlation between blood CT value and Hb concentration. The relationship of increased vascular density to degrees of cyanosis was analysed by Spearman. Results: Among 82 patients, 12 patients (14.6%) were found in the group of normal vascular density and 70 patients (85.4%) in the increased vascular density group. Among 70 patients with increased vascular density, 22 patients (26.8% ) with (55.4 ± 2.6) HU, (169 ±6)g/L of Hb, (5.8 ±0.3) × 10 12 /L of RBC and 0.51 ±0.03 of HCT, 29 patients (35.4%) with (61.3 ± 2.9) HU, (209 ± 15 ) g/L, (7.1 ± 0.4) × 10 12 /L, 0.66 ± 0.06 and 19 patients (23.2%) with (68.8 ± 4.2) HU, (242 ± 23) g/L, (8.3 ± 0.9) × 10 12 /L, 0.78 ± 0.08 were observed in the mild,moderate and severe group,respectively. There were significant differences in distribution of blood CT value (HU), Hb, RBC and HCT in different groups (F=163.263, 134.703, 120.974, 136.541; P<0.01). Blood CT value was positively correlated with Hb concentration (r=0.98, P<0.01). Vascular density was also positively correlated with the degree of cyanosis (r=0.86, P<0.01). Conclusions: Cerebral vascular density of patients suffering from CCHD presented different levels of increases based on CT scan results due to rise of RBC stimulated by anoxia. The increased level of vascular

  8. Hemifacial Pain and Hemisensory Disturbance Referred from Occipital Neuralgia Caused by Pathological Vascular Contact of the Greater Occipital Nerve.

    Science.gov (United States)

    Son, Byung-Chul; Choi, Jin-Gyu

    2017-01-01

    Here we report a unique case of chronic occipital neuralgia caused by pathological vascular contact of the left greater occipital nerve. After 12 months of left-sided, unremitting occipital neuralgia, a hypesthesia and facial pain developed in the left hemiface. The decompression of the left greater occipital nerve from pathological contacts with the occipital artery resulted in immediate relief for hemifacial sensory change and facial pain, as well as chronic occipital neuralgia. Although referral of pain from the stimulation of occipital and cervical structures innervated by upper cervical nerves to the frontal head of V1 trigeminal distribution has been reported, the development of hemifacial sensory change associated with referred trigeminal pain from chronic occipital neuralgia is extremely rare. Chronic continuous and strong afferent input of occipital neuralgia caused by pathological vascular contact with the greater occipital nerve seemed to be associated with sensitization and hypersensitivity of the second-order neurons in the trigeminocervical complex, a population of neurons in the C2 dorsal horn characterized by receiving convergent input from dural and cervical structures.

  9. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies.

    Science.gov (United States)

    Venkat, Poornima; Chopp, Michael; Zacharek, Alex; Cui, Chengcheng; Zhang, Li; Li, Qingjiang; Lu, Mei; Zhang, Talan; Liu, Amy; Chen, Jieli

    2017-02-01

    We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Pathological Gambling and Associated Drug and Alcohol Abuse, Emotion Regulation, and Anxious-Depressive Symptomatology.

    Science.gov (United States)

    Jauregui, Paula; Estévez, Ana; Urbiola, Irache

    2016-06-01

    Background and aims Pathological gambling is associated with comorbid disorders, such as anxiety, depression, and drug and alcohol abuse. Difficulties of emotion regulation may be one of the factors related to the presence of addictive disorders, along with comorbid symptomatology in pathological gamblers. Therefore, the aim of this study was to evaluate the difficulties of emotion regulation, drug and alcohol abuse, and anxious and depressive symptomatology in pathological gamblers, and the mediating role of difficulties of emotion regulation between anxiety and pathological gambling. Methods The study sample included 167 male pathological gamblers (mean age = 39.29 years) and 107 non-gamblers (mean age = 33.43 years). Pathological gambling (SOGS), difficulties of emotion regulation (DERS), drug and alcohol abuse (MUTICAGE CAD-4), and anxious and depressive symptomatology (SA-45) were measured. Student's t, Pearson's r, stepwise multiple linear regression and multiple mediation analyses were conducted. The study was approved by an Investigational Review Board. Results Relative to non-gamblers, pathological gamblers exhibited greater difficulties of emotion regulation, as well as more anxiety, depression, and drug abuse. Moreover, pathological gambling correlated with emotion regulation difficulties, anxiety, depression, and drug abuse. Besides, emotion regulation difficulties correlated with and predicted pathological gambling, drug and alcohol abuse, and anxious and depressive symptomatology. Finally, emotion regulation difficulties mediated the relationship between anxiety and pathological gambling controlling the effect of age, both when controlling and not controlling for the effect of other abuses. Discussion and conclusions These results suggest that difficulties of emotion regulation may provide new keys to understanding and treating pathological gambling and comorbid disorders.

  11. Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow.

    Science.gov (United States)

    Li, Hongmei; Guo, Qinxi; Inoue, Taeko; Polito, Vinicia A; Tabuchi, Katsuhiko; Hammer, Robert E; Pautler, Robia G; Taffet, George E; Zheng, Hui

    2014-08-09

    Accumulation and deposition of β-amyloid peptides (Aβ) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, Aβ is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aβ transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aβ and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background. Introduction of the Dutch mutation results in robust CAA and parenchymal Aβ pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology. Our study reveals a direct and positive link between vascular and parenchymal Aβ; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aβ pathology and behavioral deficits in the absence of APP overexpression.

  12. Tetraspanin CD9 regulates cell contraction and actin arrangement via RhoA in human vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Michael J Herr

    Full Text Available The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes. Upon knocking down CD9, the cells developed an abnormally small and rounded morphology. We determined that this morphological change was due to a lack of typical parallel actin arrangement. We also found similar total RhoA but decreased GTP-bound (active RhoA levels in CD9 deficient cells. As a result, cells lacking a full complement of CD9 were less contractile than their control treated counterparts. Upon restoration of RhoA activity in the CD9 deficient cells, the phenotype was reversed and cell contraction was restored. Conversely, inhibition of RhoA activity in the control cells mimicked the CD9-deficient cell phenotype. Thus, alteration in CD9 expression was sufficient to profoundly disrupt cellular actin arrangement and endogenous cell contraction by interfering with RhoA signaling. This study provides insight into how CD9 may regulate previously described vascular smooth muscle cell pathophysiology.

  13. Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.

    Science.gov (United States)

    Jakobsson, Lars; van Meeteren, Laurens A

    2013-05-15

    Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor β (TGF-β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-β family in the mouse. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Contrast-enhanced power Doppler endosonography and pathological assessment of vascularization in advanced gastric carcinomas--a feasibility study.

    Science.gov (United States)

    Iordache, Sevastiţa; Filip, Maria-Monalisa; Georgescu, Claudia-Valentina; Angelescu, Cristina; Ciurea, Tudorel; Săftoiu, Adrian

    2012-06-01

    Besides representing angiogenesis markers, microvascular density (MVD) and vascular endothelial growth factor (VEGF) are two important tools for the assessment of prognosis in patients with gastric cancer. The aim of our study was to assess the Doppler parameters (resistivity and pulsatility indexes) and vascularity index (VI) calculated by contrast-enhanced power Doppler endoscopic ultrasound (CEPD-EUS) in correlation with the expression of intra-tumoral MVD and VEGF in patients with gastric cancer. The study included 20 consecutive patients with advanced gastric carcinoma, but without distant metastasis at initial assessment. All the patients were assessed by contrast-enhanced power Doppler endoscopic ultrasound (EUS) combined with pulsed Doppler examinations in the late venous phase. The vascularity index (VI) was calculated before and after injection of second generation microbubble contrast specific agent (SonoVue 2.4 mL), used as a Doppler signal enhancer. Moreover, pulsed Doppler parameters (resistivity and pulsatility indexes) were further calculated. The correlation between power Doppler parameters and pathological/molecular parameters (MVD assessed through immunohistochemistry with CD31 and CD34, as well as VEGF assessed through real-time PCR) was assessed. Kaplan-Meier survival analysis was used for the assessment of prognosis. Significantly statistical correlations were found between post-contrast VI and CD34 (p=0.0226), VEGF (p=0.0231), VEGF-A (p=0.0464) and VEGF-B (p=0.0022) while pre-contrast VI was correlated only with CD34 expression. Pulsatility index and resistivity index were not correlated with MVD or VEGF expression. Survival analysis demonstrated that VEGF-A is an accurate parameter for survival rate (p=0.045), as compared to VEGF (p=0.085) and VEGF-B (p=0.230). We did not find any correlation between the survival rate and ultrasound parameters (RI, PI, pre-contrast VI or post-contrast VI). Assessment of tumor vascularity using contrast

  15. Phosphodiesterase 1 regulation is a key mechanism in vascular aging

    DEFF Research Database (Denmark)

    Niño, Paula K Bautista; Durik, Matej; Danser, A H Jan

    2015-01-01

    Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role...... in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d...... in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated...

  16. CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Castellot John J

    2003-11-01

    Full Text Available Abstract Background Vascular smooth muscle cell (VSMC hyperplasia plays an important role in both chronic and acute vascular pathologies including atherosclerosis and restenosis. Considerable work has focused on the mechanisms regulating VSMC proliferation and motility. Earlier work in our lab revealed a novel growth arrest-specific (gas gene induced in VSMC exposed to the antiproliferative agent heparin. This gene is a member of the CCN family and has been given the name CCN5. The objective of the present study is to elucidate the function of CCN5 protein and to explore its mechanism of action in VSMC. Results Using RNA interference (RNAi, we first demonstrate that CCN5 is required for the antiproliferative effect of heparin in VSMC. We also use this gene knockdown approach to show that CCN5 is an important negative regulator of motility. To explore the mechanism of action of CCN5 on VSMC motility, we use RNAi to demonstrate that knock down of CCN5 up regulates expression of matrix metalloproteinase-2 (MMP-2, an important stimulator of motility in VSMC. In addition, forced expression of CCN5 via adenovirus results in reduced MMP-2 activity, this also corroborates the gene knock down results. Finally, we show that loss of CCN5 expression in VSMC causes changes in VSMC morphology and cytoskeletal organization, including a reduction in the amount and macromolecular assembly of smooth muscle cell α-actin. Conclusions This work provides important new insights into the regulation of smooth muscle cell proliferation and motility by CCN5 and may aid the development of therapies for vascular diseases.

  17. Orphan Nuclear Receptor Nur77 Is a Novel Negative Regulator of Endothelin-1 Expression In Vascular Endothelial Cells

    OpenAIRE

    Qin, Qing; Chen, Ming; Yi, Bing; You, Xiaohua; Yang, Ping; Sun, Jianxin

    2014-01-01

    Endothelin-1 (ET-1) produced by vascular endothelial cells plays essential roles in the regulation of vascular tone and development of cardiovascular diseases. The objective of this study is to identify novel regulators implicated in the regulation of ET-1 expression in vascular endothelial cells (ECs). By using quantitative real-time PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA), we show that either ectopic expression of orphan nuclear receptor Nur77 or pharmacological activati...

  18. Eating pathology, emotion regulation, and emotional overeating in obese adults with Binge Eating Disorder.

    Science.gov (United States)

    Gianini, Loren M; White, Marney A; Masheb, Robin M

    2013-08-01

    The purpose of the current study was to examine the relationship among emotional regulation, emotional overeating, and general eating pathology in a treatment seeking sample of adults with Binge Eating Disorder (BED). The sample was composed of 326 adults (248 women, 78 men) who were obese and met DSM-IV-TR criteria for BED. Prior to treatment, participants completed the Difficulties in Emotion Regulation Scale (DERS), Emotional Overeating Questionnaire (EOQ), Beck Depression Inventory (BDI), and Eating Disorder Examination-Questionnaire (EDE-Q) as part of a larger assessment battery. A series of hierarchical regression analyses indicated that difficulties with emotion regulation accounted for unique variance in both emotional overeating and general eating pathology above and beyond sex and negative affect. Emotion regulation may play a significant role in the maintenance of emotional overeating and eating pathology in obese adults with BED. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Flow regulation in coronary vascular tree: a model study.

    Directory of Open Access Journals (Sweden)

    Xinzhou Xie

    Full Text Available Coronary blood flow can always be matched to the metabolic demand of the myocardium due to the regulation of vasoactive segments. Myocardial compressive forces play an important role in determining coronary blood flow but its impact on flow regulation is still unknown. The purpose of this study was to develop a coronary specified flow regulation model, which can integrate myocardial compressive forces and other identified regulation factors, to further investigate the coronary blood flow regulation behavior.A theoretical coronary flow regulation model including the myogenic, shear-dependent and metabolic responses was developed. Myocardial compressive forces were included in the modified wall tension model. Shear-dependent response was estimated by using the experimental data from coronary circulation. Capillary density and basal oxygen consumption were specified to corresponding to those in coronary circulation. Zero flow pressure was also modeled by using a simplified capillary model.Pressure-flow relations predicted by the proposed model are consistent with previous experimental data. The predicted diameter changes in small arteries are in good agreement with experiment observations in adenosine infusion and inhibition of NO synthesis conditions. Results demonstrate that the myocardial compressive forces acting on the vessel wall would extend the auto-regulatory range by decreasing the myogenic tone at the given perfusion pressure.Myocardial compressive forces had great impact on coronary auto-regulation effect. The proposed model was proved to be consistent with experiment observations and can be employed to investigate the coronary blood flow regulation effect in physiological and pathophysiological conditions.

  20. Morphometric analysis of vascular pathology in the orbitofrontal cortex of older subjects with major depression.

    Science.gov (United States)

    Miguel-Hidalgo, Jose Javier; Jiang, Wei; Konick, Lisa; Overholser, James C; Jurjus, George J; Stockmeier, Craig A; Steffens, David C; Krishnan, K Ranga R; Rajkowska, Grazyna

    2013-09-01

    Late-life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late-life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. The present study used a non-specific histological Nissl staining and a more vessel-specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 older subjects with major depressive disorder (MDD) and 9 non-psychiatric comparison subjects. The density of Nissl-stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF-immunoreactive segments with cross-sectional areas greater than 800 µm2 was higher in MDD. In WM, only the density of vWF-immunoreactive segments with patent perivascular spaces and diameters larger than 60 µm was higher in subjects with MDD. Also in the WM, only subjects with late-onset MDD presented a significantly higher density of vWF-positive segments than comparison subjects. In older subjects with MDD, there appear to be morphological changes that increase visibility of medium-sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles. Copyright © 2012 John Wiley & Sons, Ltd.

  1. MORPHOMETRIC ANALYSIS OF VASCULAR PATHOLOGY IN THE ORBITOFRONTAL CORTEX OF ELDERLY SUBJECTS WITH MAJOR DEPRESSION

    Science.gov (United States)

    Miguel-Hidalgo, Jose Javier; Jiang, Wei; Konick, Lisa; Overholser, James C.; Jurjus, George J.; Stockmeier, Craig A.; Steffens, David; Krishnan, K. Ranga R.; Rajkowska, Grazyna

    2012-01-01

    Objective Late-life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late-life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. Methods The present study used a non-specific histological Nissl staining and a more vessel-specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 elderly subjects with major depressive disorder (MDD) and 9 non-psychiatric comparison subjects. Results The density of Nissl-stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF-immunoreactive segments with cross-sectional areas greater than 800 μm2 was higher in MDD. In WM, only the density of vWF-immunoreactive segments with patent perivascular spaces and diameters larger than 60 μm was higher in subjects with MDD. Also in the WM, only subjects with late-onset MDD presented a significantly higher density of vWF-positive segments than comparison subjects. Conclusions In elderly subjects with MDD, there appear to be morphological changes that increase visibility of medium-sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles. PMID:23208772

  2. ROBO4-Mediated Vascular Integrity Regulates the Directionality of Hematopoietic Stem Cell Trafficking

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    Stephanie Smith-Berdan

    2015-02-01

    Full Text Available Despite the use of hematopoietic stem cells (HSCs in clinical therapy for over half a century, the mechanisms that regulate HSC trafficking, engraftment, and life-long persistence after transplantation are unclear. Here, we show that the vascular endothelium regulates HSC trafficking into and out of bone marrow (BM niches. Surprisingly, we found that instead of acting as barriers to cellular entry, vascular endothelial cells, via the guidance molecule ROBO4, actively promote HSC translocation across vessel walls into the BM space. In contrast, we found that the vasculature inhibits the reverse process, as induced vascular permeability led to a rapid increase in HSCs in the blood stream. Thus, the vascular endothelium reinforces HSC localization to BM niches both by promoting HSC extravasation from blood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. Our results uncouple the mechanisms that regulate the directionality of HSC trafficking and show that the vasculature can be targeted to improve hematopoietic transplantation therapies.

  3. Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis.

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    Sanja Coso

    Full Text Available BACKGROUND: Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF family is a major regulator of lymphatic endothelial cell (LEC function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. METHODS AND RESULTS: Here we delineate the VEGF-C/VEGF receptor (VEGFR-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. CONCLUSIONS: Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.

  4. Micro Vascular Plug (MVP)-assisted vessel occlusion in neurovascular pathologies: technical results and initial clinical experience.

    Science.gov (United States)

    Beaty, Narlin B; Jindal, Gaurav; Gandhi, Dheeraj

    2015-10-01

    Deconstructive approaches may be necessary to treat a variety of neurovascular pathologies. Recently, a new device has become available for endovascular arterial occlusion that may have unique applications in neurovascular disease. The Micro Vascular Plug (MVP, Reverse Medical, Irvine, California, USA) has been designed for vessel occlusion through targeted embolization. To report the results from our initial experience with eight consecutive patients in whom the MVP was used to achieve endovascular occlusion of an artery in the head and neck. Eight consecutive patients treated over a nine-month period were included. The patients' radiographic and electronic medical records were retrospectively reviewed. Specifically demographic information, clinical indication, site of arterial occlusion, size of MVP, time to vessel occlusion, clinical complications, use of other secondary embolic agents, and clinical outcome were recorded. Follow-up information when available is presented. The MVP was used in eight patients for the treatment of neurovascular disease. Indications for treatment included post-traumatic head/neck bleeding (n=3), carotid-cavernous fistula (1), vertebral-vertebral fistula (1), giant fusiform vertebral aneurysm (1), stump-emboli after carotid dissection (1), and iatrogenic vertebral artery penetrating injury (1). One device was used in five patients, two in two patients, and one patient with extensive vertebral-vertebral venous fistula required three plugs to effectively trap the fistula from proximal and distal aspects. Vessel occlusion was obtained in MVP in neurovascular disease. Use of this device may be associated with shorter procedural times and cost savings in comparison with the use of microcoils for vessel occlusion. Our experience shows that MVP can have unique applications in neurovascular pathologies and it complements other occlusive devices. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted

  5. Retinal vascular pathology risk development in the irradiated at different ages as a result if Chornobyl NPP accident

    International Nuclear Information System (INIS)

    Fedyirko, P.A.; Babenko, T.F.; Doryichevs'ka, R.Yu.; Gar'kava, N.A.

    2015-01-01

    The object of the study was the state of the retinal vessels in 2,531 persons (1,948 evacuated from the city of Pripyat under the age of 20 and 583 exposed to radiation in utero as a result of the Chornobyl NPP disaster. The results of standardized ophthalmic examination conducted from 1993 to 2000 within the framework of Clinical and epidemiological registry are used for the analysis. The evacuees were subdivided into different age groups of the exposed to radiation. The cohort of control group formed corresponding age groups of the unirradiated control. Statistical analysis of the survey results was carried out using the free trial version of ''Open Epi 2.2.1'' software package. The results obtained revealed a significant prevalence of retinal vessels pathology in all groups. The difference in angiopathy prevalence in exposed in utero persons was significant compared to age control. The prevalence of retinal vascular pathology was also significantly higher in all groups of evacuees. Angiopathy prevalence was higher in the group exposed in utero and at the age of 8-12 years, and in the group of people who were exposed at the age of 4-7 years, the risk of angiopathy was lower. It is proved that the occurrence of distant radiation effects mainly depends on the age at which a person has undergone irradiation. It should be noted that all the other conditions were approximately the same. If working conditions of the persons who were exposed in utero or were aged 8 to 20 years when the Chornobyl disaster happened are connected with occupational radiation exposure it is necessary to take additional preventive measures

  6. RETINAL VASCULAR PATHOLOGY RISK DEVELOPMENT IN THE IRRADIATED AT DIFFERENT AGES AS A RESULT OF CHERNOBYL NPP ACCIDENT.

    Science.gov (United States)

    Fedirko, P A; Babenko, T F; Dorichevska, R Yu; Garkava, N A

    2015-12-01

    To assess the relationship between the age at which a person undergoes radiation exposure and risk of developing eye lesions (case study of the retinal angiopathy prevalence). The object of the study was the state of the retinal vessels in 2,531 persons (1,948 evacuated from the city of Pripyat under the age of 20 and 583 exposed to radiation in utero as a result of the Chernobyl NPP disaster. The results of standardized ophthalmic examination conducted from 1993 to 2000 within the framework of Clinical and epidemiological registry are used for the analysis. The evacuees were subdivided into different age groups of the exposed to radiation. The cohort of control group formed corresponding age groups of the unirradiated control. Statistical analysis of the survey results was carried out using the free trial version of «Open Epi 2.2.1» software package. The results obtained revealed a significant prevalence of retinal vessels pathology in all groups. The difference in angiopathy prevalence in exposed in utero persons was significant compared to age-control. The prevalence of retinal vascular pathology was also significantly higher in all groups of evacuees. Angiopathy prevalence was higher in the group exposed in utero and at the age of 8-12 years, and in the group of people who were exposed at the age of 4-7 years, the risk of angiopathy was lower. It is proved that the occurrence of distant radiation effects mainly depends on the age at which a person has undergone irradiation. It should be noted that all the other conditions were approximately the same. If working conditions of the persons who were exposed in utero or were aged 8 to 20 years when the Chernobyl disaster happened are connected with occupational radiation exposure it is necessary to take additional preventive measures. P. А. Fedirko, T. F. Babenko, R. Yu. Dorichevska, N. А. Garkava.

  7. Hsp90 molecular chaperone: structure, functions and participation in cardio-vascular pathologies

    Directory of Open Access Journals (Sweden)

    Kroupskaya I. V.

    2009-10-01

    Full Text Available The review is devoted to the analysis of structural and functional properties of molecular chaperon Hsp90. Hsp90 is a representative of highly widespread family of heat shock proteins. The protein is found in eubacteria and all branches of eukarya, but it is apparently absent in archaea. It is one of key regulators of numerous signalling pathways, cell growth and development, apoptosis, induction of autoimmunity, and progression of heart failure. The full functional activity of Hsp90 shows up in a complex with other molecular chaperones and co-chaperones. Molecular interactions between chaperones, different signalling proteins and protein-partners are highly crucial for the normal functioning of signalling pathways and their destruction causes an alteration in the cell physiology up to its death.

  8. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

    Science.gov (United States)

    Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

    2016-10-13

    The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

  9. Vascular endothelial growth factor signaling regulates the segregation of artery and vein via ERK activity during vascular development

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Se-Hee [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Schmitt, Christopher E.; Woolls, Melissa J. [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States); Holland, Melinda B. [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Kim, Jun-Dae [Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States); Jin, Suk-Won, E-mail: suk-won.jin@yale.edu [Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States)

    2013-01-25

    Highlights: ► VEGF-A signaling regulates the segregation of axial vessels. ► VEGF-A signaling is mediated by PKC and ERK in this process. ► Ectopic activation of ERK is sufficient to rescue defects in vessel segregation. -- Abstract: Segregation of two axial vessels, the dorsal aorta and caudal vein, is one of the earliest patterning events occur during development of vasculature. Despite the importance of this process and recent advances in our understanding on vascular patterning during development, molecular mechanisms that coordinate the segregation of axial vessels remain largely elusive. In this report, we find that vascular endothelial growth factor-A (Vegf-A) signaling regulates the segregation of dorsal aorta and axial vein during development. Inhibition of Vegf-A pathway components including ligand Vegf-A and its cognate receptor Kdrl, caused failure in segregation of axial vessels in zebrafish embryos. Similarly, chemical inhibition of Mitogen-activated protein kinase kinase (Map2k1)/Extracellular-signal-regulated kinases (Erk) and phosphatidylinositol 3-kinases (PI3 K), which are downstream effectors of Vegf-A signaling pathway, led to the fusion of two axial vessels. Moreover, we find that restoring Erk activity by over-expression of constitutively active MEK in embryos with a reduced level of Vegf-A signaling can rescue the defects in axial vessel segregation. Taken together, our data show that segregation of axial vessels requires the function of Vegf-A signaling, and Erk may function as the major downstream effector in this process.

  10. Vascular endothelial growth factor signaling regulates the segregation of artery and vein via ERK activity during vascular development

    International Nuclear Information System (INIS)

    Kim, Se-Hee; Schmitt, Christopher E.; Woolls, Melissa J.; Holland, Melinda B.; Kim, Jun-Dae; Jin, Suk-Won

    2013-01-01

    Highlights: ► VEGF-A signaling regulates the segregation of axial vessels. ► VEGF-A signaling is mediated by PKC and ERK in this process. ► Ectopic activation of ERK is sufficient to rescue defects in vessel segregation. -- Abstract: Segregation of two axial vessels, the dorsal aorta and caudal vein, is one of the earliest patterning events occur during development of vasculature. Despite the importance of this process and recent advances in our understanding on vascular patterning during development, molecular mechanisms that coordinate the segregation of axial vessels remain largely elusive. In this report, we find that vascular endothelial growth factor-A (Vegf-A) signaling regulates the segregation of dorsal aorta and axial vein during development. Inhibition of Vegf-A pathway components including ligand Vegf-A and its cognate receptor Kdrl, caused failure in segregation of axial vessels in zebrafish embryos. Similarly, chemical inhibition of Mitogen-activated protein kinase kinase (Map2k1)/Extracellular-signal-regulated kinases (Erk) and phosphatidylinositol 3-kinases (PI3 K), which are downstream effectors of Vegf-A signaling pathway, led to the fusion of two axial vessels. Moreover, we find that restoring Erk activity by over-expression of constitutively active MEK in embryos with a reduced level of Vegf-A signaling can rescue the defects in axial vessel segregation. Taken together, our data show that segregation of axial vessels requires the function of Vegf-A signaling, and Erk may function as the major downstream effector in this process

  11. Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy.

    Science.gov (United States)

    Galan, Alba; Barcelona, Pablo F; Nedev, Hinyu; Sarunic, Marinko V; Jian, Yifan; Saragovi, H Uri

    2017-06-01

    The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. We compared the pharmacokinetics of a single 40 μg subconjunctival (SCJ) depot to the reported effective 5 μg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.

  12. Vascular pattern of the dentate gyrus is regulated by neural progenitors.

    Science.gov (United States)

    Pombero, Ana; Garcia-Lopez, Raquel; Estirado, Alicia; Martinez, Salvador

    2018-05-01

    Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG.

  13. Impulsivity, self-regulation,and pathological video gaming among youth: testing a mediation model.

    Science.gov (United States)

    Liau, Albert K; Neo, Eng Chuan; Gentile, Douglas A; Choo, Hyekyung; Sim, Timothy; Li, Dongdong; Khoo, Angeline

    2015-03-01

    Given the potential negative mental health consequences of pathological video gaming, understanding its etiology may lead to useful treatment developments. The purpose of the study was to examine the influence of impulsive and regulatory processes on pathological video gaming. Study 1 involved 2154 students from 6 primary and 4 secondary schools in Singapore. Study 2 involved 191 students from 2 secondary schools. The results of study 1 and study 2 supported the hypothesis that self-regulation is a mediator between impulsivity and pathological video gaming. Specifically, higher levels of impulsivity was related to lower levels of self-regulation, which in turn was related to higher levels of pathological video gaming. The use of impulsivity and self-regulation in predicting pathological video gaming supports the dual-system model of incorporating both impulsive and reflective systems in the prediction of self-control outcomes. The study highlights the development of self-regulatory resources as a possible avenue for future prevention and treatment research. © 2011 APJPH.

  14. Differential regulation of protease activated receptor-1 and tissue plasminogen activator expression by shear stress in vascular smooth muscle cells

    Science.gov (United States)

    Papadaki, M.; Ruef, J.; Nguyen, K. T.; Li, F.; Patterson, C.; Eskin, S. G.; McIntire, L. V.; Runge, M. S.

    1998-01-01

    Recent studies have demonstrated that vascular smooth muscle cells are responsive to changes in their local hemodynamic environment. The effects of shear stress on the expression of human protease activated receptor-1 (PAR-1) and tissue plasminogen activator (tPA) mRNA and protein were investigated in human aortic smooth muscle cells (HASMCs). Under conditions of low shear stress (5 dyn/cm2), PAR-1 mRNA expression was increased transiently at 2 hours compared with stationary control values, whereas at high shear stress (25 dyn/cm2), mRNA expression was decreased (to 29% of stationary control; Pmuscle cells, indicating that the effects of shear stress on human PAR-1 were not species-specific. Flow cytometry and ELISA techniques using rat smooth muscle cells and HASMCs, respectively, provided evidence that shear stress exerted similar effects on cell surface-associated PAR-1 and tPA protein released into the conditioned media. The decrease in PAR-1 mRNA and protein had functional consequences for HASMCs, such as inhibition of [Ca2+] mobilization in response to thrombin stimulation. These data indicate that human PAR-1 and tPA gene expression are regulated differentially by shear stress, in a pattern consistent with their putative roles in several arterial vascular pathologies.

  15. Nitric oxide (NO) in normal and hypoxic vascular regulation of the spiny dogfish, Squalus acanthias.

    Science.gov (United States)

    Swenson, Kai E; Eveland, Randy L; Gladwin, Mark T; Swenson, Erik R

    2005-02-01

    Nitric oxide (NO) is a potent vasodilator in terrestrial vertebrates, but whether vascular endothelial-derived NO plays a role in vascular regulation in fish remains controversial. To explore this issue, a study was made of spiny dogfish sharks (Squalus acanthias) in normoxia and acute hypoxia (60 min exposure to seawater equilibrated with 3% oxygen) with various agents known to alter NO metabolism or availability. In normoxia, nitroprusside (a NO donor) reduced blood pressure by 20%, establishing that vascular smooth muscle responds to NO. L-arginine, the substrate for NO synthase, had no hemodynamic effect. Acetylcholine, which stimulates endothelial NO and prostaglandin production in mammals, reduced blood pressure, but also caused marked bradycardia. L-NAME, an inhibitor of all NO synthases, caused a small 10% rise in blood pressure, but cell-free hemoglobin (a potent NO scavenger and hypertensive agent in mammals) had no effect. Acute hypoxia caused a 15% fall in blood pressure, which was blocked by L-NAME and cell-free hemoglobin. Serum nitrite, a marker of NO production, rose with hypoxia, but not with L-NAME. Results suggest that NO is not an endothelial-derived vasodilator in the normoxic elasmobranch. The hypertensive effect of L-NAME may represent inhibition of NO production in the CNS and nerves regulating blood pressure. In acute hypoxia, there is a rapid up-regulation of vascular NO production that appears to be responsible for hypoxic vasodilation.

  16. Insecure Attachment and Eating Pathology in Early Adolescence: Role of Emotion Regulation

    Science.gov (United States)

    van Durme, Kim; Braet, Caroline; Goossens, Lien

    2015-01-01

    The present study investigated whether associations exist between attachment dimensions toward mother and different forms of eating pathology (EP) in a group of early adolescent boys and girls, and whether these associations were mediated by maladaptive emotion regulation (ER) strategies. Developmentally appropriate self-report questionnaires were…

  17. SODIUM-POTASSIUM-CHLORIDE COTRANSPORT IN THE REGULATION OF VASCULAR MYOGENIC TONE

    Directory of Open Access Journals (Sweden)

    S. N. Orlov

    2014-01-01

    Full Text Available The article discusses the data on the functioning of Na+,K+,2Cl– cotransport – the carrier providing electroneutral symport of sodium, potassium and chloride, as well as molecular mechanisms of the regulation and physiological significance of this carrier. We analyzed the novel data on involvement of ubiquitous isoform of Na+,K+,2Cl–cotransporter (NKCC1 in regulation of vascular smooth muscle contraction, and role of this carrier in the regulation of cell volume and intracellular chloride concentration.

  18. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    International Nuclear Information System (INIS)

    Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

    2012-01-01

    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

  19. GSK-3α is a central regulator of age-related pathologies in mice.

    Science.gov (United States)

    Zhou, Jibin; Freeman, Theresa A; Ahmad, Firdos; Shang, Xiying; Mangano, Emily; Gao, Erhe; Farber, John; Wang, Yajing; Ma, Xin-Liang; Woodgett, James; Vagnozzi, Ronald J; Lal, Hind; Force, Thomas

    2013-04-01

    Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3α, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3α is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3α activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies.

  20. Peptide-modified PELCL electrospun membranes for regulation of vascular endothelial cells

    International Nuclear Information System (INIS)

    Zhou, Fang; Jia, Xiaoling; Yang, Yang; Yang, Qingmao; Gao, Chao; Zhao, Yunhui; Fan, Yubo; Yuan, Xiaoyan

    2016-01-01

    The efficiency of biomaterials used in small vascular repair depends greatly on their ability to interact with vascular endothelial cells (VECs). Rapid endothelialization of the vascular grafts is a promising way to prevent thrombosis and intimal hyperplasia. In this work, modification of electrospun membranes of poly(ethylene glycol)-b-poly(L-lactide-co-ε-caprolactone) (PELCL) by three different peptides for regulation of VECs were studied in order to obtain ideal bioactive biomaterials as small diameter vascular grafts. QK (a mimetic peptide to vascular endothelial growth factor), Arg-Glu-Asp-Val (REDV, a specific adhesive peptide to VECs) and Val-Ala-Pro-Gly (VAPG, a specific adhesive peptide to vascular smooth muscle cells) were investigated. Surface properties of the modified membranes and the response of VECs were verified. It was found that protein adsorption and platelet adhesion were effectively suppressed with the introduction of QK, REDV or VAPG peptides on the PELCL electrospun membranes. Both QK- and REDV-modified electrospun membranes could accelerate the proliferation of VECs in the first 9 days, and the QK-modified electrospun membrane promoted cell proliferation more significantly than the REDV-modified one. The REDV-modified PELCL membrane was the most favorable for VECs adhesion than QK- and VAPG-modified membranes. It was suggested that QK- or REDV-modified PELCL electrospun membranes may have great potential applications in cardiovascular biomaterials for rapid endothelialization in situ. - Highlights: • A series of peptide-modified PELCL electrospun membranes were prepared. • Hemocompatibility of the membranes was greatly improved by the modification. • QK-modified PELCL membrane promoted VECs proliferation more significantly. • REDV-modified PELCL membrane was the most favorable for VEC adhesion.

  1. Peptide-modified PELCL electrospun membranes for regulation of vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Fang [School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300072 (China); Jia, Xiaoling [Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083 (China); Yang, Yang [School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300072 (China); Yang, Qingmao; Gao, Chao [Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083 (China); Zhao, Yunhui [School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300072 (China); Fan, Yubo, E-mail: yubofan@buaa.edu.cn [Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083 (China); National Research Center for Rehabilitation Technical Aids, Beijing 100176 (China); Yuan, Xiaoyan, E-mail: yuanxy@tju.edu.cn [School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300072 (China)

    2016-11-01

    The efficiency of biomaterials used in small vascular repair depends greatly on their ability to interact with vascular endothelial cells (VECs). Rapid endothelialization of the vascular grafts is a promising way to prevent thrombosis and intimal hyperplasia. In this work, modification of electrospun membranes of poly(ethylene glycol)-b-poly(L-lactide-co-ε-caprolactone) (PELCL) by three different peptides for regulation of VECs were studied in order to obtain ideal bioactive biomaterials as small diameter vascular grafts. QK (a mimetic peptide to vascular endothelial growth factor), Arg-Glu-Asp-Val (REDV, a specific adhesive peptide to VECs) and Val-Ala-Pro-Gly (VAPG, a specific adhesive peptide to vascular smooth muscle cells) were investigated. Surface properties of the modified membranes and the response of VECs were verified. It was found that protein adsorption and platelet adhesion were effectively suppressed with the introduction of QK, REDV or VAPG peptides on the PELCL electrospun membranes. Both QK- and REDV-modified electrospun membranes could accelerate the proliferation of VECs in the first 9 days, and the QK-modified electrospun membrane promoted cell proliferation more significantly than the REDV-modified one. The REDV-modified PELCL membrane was the most favorable for VECs adhesion than QK- and VAPG-modified membranes. It was suggested that QK- or REDV-modified PELCL electrospun membranes may have great potential applications in cardiovascular biomaterials for rapid endothelialization in situ. - Highlights: • A series of peptide-modified PELCL electrospun membranes were prepared. • Hemocompatibility of the membranes was greatly improved by the modification. • QK-modified PELCL membrane promoted VECs proliferation more significantly. • REDV-modified PELCL membrane was the most favorable for VEC adhesion.

  2. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition.

    Science.gov (United States)

    Findeisen, Hannes M; Gizard, Florence; Zhao, Yue; Qing, Hua; Heywood, Elizabeth B; Jones, Karrie L; Cohn, Dianne; Bruemmer, Dennis

    2011-04-01

    Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive. In the present study, we investigated the role of histone deacetylase (HDAC) inhibition in SMC proliferation and neointimal remodeling. We demonstrate that mitogens induce transcription of HDAC 1, 2, and 3 in SMC. Short interfering RNA-mediated knockdown of either HDAC 1, 2, or 3 and pharmacological inhibition of HDAC prevented mitogen-induced SMC proliferation. The mechanisms underlying this reduction of SMC proliferation by HDAC inhibition involve a growth arrest in the G(1) phase of the cell cycle that is due to an inhibition of retinoblastoma protein phosphorylation. HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). Furthermore, HDAC inhibition repressed mitogen-induced cyclin D1 mRNA expression and cyclin D1 promoter activity. As a result of this differential cell cycle-regulatory gene expression by HDAC inhibition, the retinoblastoma protein retains a transcriptional repression of its downstream target genes required for S phase entry. Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury. These findings identify HDAC as a critical component of a transcriptional cascade regulating SMC proliferation and suggest that HDAC might play a pivotal role in the development of proliferative vascular diseases, including atherosclerosis and in-stent restenosis.

  3. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia.

    Science.gov (United States)

    Zhao, Lan; Oliver, Eduardo; Maratou, Klio; Atanur, Santosh S; Dubois, Olivier D; Cotroneo, Emanuele; Chen, Chien-Nien; Wang, Lei; Arce, Cristina; Chabosseau, Pauline L; Ponsa-Cobas, Joan; Frid, Maria G; Moyon, Benjamin; Webster, Zoe; Aldashev, Almaz; Ferrer, Jorge; Rutter, Guy A; Stenmark, Kurt R; Aitman, Timothy J; Wilkins, Martin R

    2015-08-20

    The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.

  4. Vascular ATP-sensitive potassium channels are over-expressed and partially regulated by nitric oxide in experimental septic shock.

    Science.gov (United States)

    Collin, Solène; Sennoun, Nacira; Dron, Anne-Gaëlle; de la Bourdonnaye, Mathilde; Montemont, Chantal; Asfar, Pierre; Lacolley, Patrick; Meziani, Ferhat; Levy, Bruno

    2011-05-01

    To study the activation and expression of vascular (aorta and small mesenteric arteries) potassium channels during septic shock with or without modulation of the NO pathway. Septic shock was induced in rats by peritonitis. Selective inhibitors of vascular K(ATP) (PNU-37883A) or BK(Ca) [iberiotoxin (IbTX)] channels were used to demonstrate their involvement in vascular hyporeactivity. Vascular response to phenylephrine was measured on aorta and small mesenteric arteries mounted on a wire myograph. Vascular expression of potassium channels was studied by PCR and Western blot, in the presence or absence of 1400W, an inducible NO synthase (iNOS) inhibitor. Aortic activation of the transcriptional factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic mobility shift assay. Arterial pressure as well as in vivo and ex vivo vascular reactivity were reduced by sepsis and improved by PNU-37883A but not by IbTX. Sepsis was associated with an up-regulation of mRNA and protein expression of vascular K(ATP) channels, while expression of vascular BK(Ca) channels remained unchanged. Selective iNOS inhibition blunted the sepsis-induced increase in aortic NO, decreased NF-κB activation, and down-regulated vascular K(ATP) channel expression. Vascular K(ATP) but not BK(Ca) channels are activated, over-expressed, and partially regulated by NO via NF-κB activation during septic shock. Their selective inhibition restores arterial pressure and vascular reactivity and decreases lactate concentration. The present data suggest that selective vascular K(ATP) channel inhibitors offer potential therapeutic perspectives for septic shock.

  5. Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking.

    Directory of Open Access Journals (Sweden)

    Anna E Daniel

    Full Text Available Plasminogen activator inhibitor-1 (PAI-1, a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact.We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus.Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall.

  6. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

    DEFF Research Database (Denmark)

    Storkebaum, Erik; Ruiz de Almodovar, Carmen; Meens, Merlijn

    2010-01-01

    BACKGROUND: Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. METHODS AND RESULTS: Here, we report that VEGF( ...

  7. WNT5A-JNK regulation of vascular insulin resistance in human obesity.

    Science.gov (United States)

    Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

    2016-12-01

    Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m 2 ) and five metabolically normal non-obese (BMI 26±2 kg/m 2 ) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. © The Author(s) 2016.

  8. Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

    Science.gov (United States)

    Majed, Batoule H.

    2012-01-01

    Prostacyclin (PGI2) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A2, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI2 is produced by endothelial cells and influences many cardiovascular processes. PGI2 acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI2 analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI2/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca2+]i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI2 intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI2 counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A2 (TXA2), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI2/TXA2 balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI2/TXA2 ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI2 activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI2 analogs in the management of pregnancy-associated and neonatal

  9. Post-transcriptional regulation of vascular endothelial growth factor: Implications for tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Peter S Yoo; Abby L Mulkeen; Charles H Cha

    2006-01-01

    Vascular endothelial growth factor (VEGF) is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization,translation, and differential cellular localization of various isoforms. Recent advances in our understanding of posttranscriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5'UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference (RNAi)technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.

  10. Vascular Function and Regulation of Blood Flow in Resting and Contracting Skeletal Muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    importance. The present work provides new insight in to vasodilator interactions important for exercise hyperemia and sheds light on mechanisms important for vascular function and regulation of skeletal muscle blood flow in essential hypertension (high blood pressure) and aging and identifies mechanisms......The precise matching of blood flow, oxygen delivery and metabolism is essential as it ensures that any increase in muscle work is precisely matched by increases in oxygen delivery. Therefore, understanding the control mechanisms of skeletal muscle blood flow regulation is of great biological...... in the regulation of exercise hyperemia. Furthermore, blood flow to contracting leg skeletal muscles is reduced both in essential hypertension and with aging. The potential difference in vasoactive system(s) responsible for the reduction in blood flow in the two conditions is in agreement with the suggestion...

  11. KCl cotransport regulation and protein kinase G in cultured vascular smooth muscle cells.

    Science.gov (United States)

    Adragna, N C; Zhang, J; Di Fulvio, M; Lincoln, T M; Lauf, P K

    2002-05-15

    K-Cl cotransport is activated by vasodilators in erythrocytes and vascular smooth muscle cells and its regulation involves putative kinase/phosphatase cascades. N-ethylmaleimide (NEM) activates the system presumably by inhibiting a protein kinase. Nitrovasodilators relax smooth muscle via cGMP-dependent activation of protein kinase G (PKG), a regulator of membrane channels and transporters. We investigated whether PKG regulates K-Cl cotransport activity or mRNA expression in normal, PKG-deficient-vector-only-transfected (PKG-) and PKG-catalytic-domain-transfected (PKG+) rat aortic smooth muscle cells. K-Cl cotransport was calculated as the Cl-dependent Rb influx, and mRNA was determined by semiquantitative RT-PCR. Baseline K-Cl cotransport was higher in PKG+ than in PKG- cells (p <0.01). At 0.5 mM, NEM stimulated K-Cl cotransport by 5-fold in PKG- but not in PKG+ cells. However, NEM was more potent although less effective to activate K-Cl cotransport in normal (passage 1-3) and PKG+ than in PKG- cells. In PKG- cells, [(dihydroindenyl) oxy] alkanoic acid (300 mM) but not furosemide (1 mM) inhibited K-Cl cotransport. Furthermore, no difference in K-Cl cotransport mRNA expression was observed between these cells. In conclusion, this study shows that manipulation of PKG expression in vascular smooth muscle cells affects K-Cl cotransport activity and its activation by NEM.

  12. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

    Science.gov (United States)

    Tanaka, Leonardo Y; Laurindo, Francisco R M

    2017-08-01

    Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases. Copyright © 2017 Elsevier Inc. All

  13. Proteolytic degradation of regulator of G protein signaling 2 facilitates temporal regulation of Gq/11 signaling and vascular contraction.

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    Kanai, Stanley M; Edwards, Alethia J; Rurik, Joel G; Osei-Owusu, Patrick; Blumer, Kendall J

    2017-11-24

    Regulator of G protein signaling 2 (RGS2) controls signaling by receptors coupled to the G q/11 class heterotrimeric G proteins. RGS2 deficiency causes several phenotypes in mice and occurs in several diseases, including hypertension in which a proteolytically unstable RGS2 mutant has been reported. However, the mechanisms and functions of RGS2 proteolysis remain poorly understood. Here we addressed these questions by identifying degradation signals in RGS2, and studying dynamic regulation of G q/11 -evoked Ca 2+ signaling and vascular contraction. We identified a novel bipartite degradation signal in the N-terminal domain of RGS2. Mutations disrupting this signal blunted proteolytic degradation downstream of E3 ubiquitin ligase binding to RGS2. Analysis of RGS2 mutants proteolyzed at various rates and the effects of proteasome inhibition indicated that proteolytic degradation controls agonist efficacy by setting RGS2 protein expression levels, and affecting the rate at which cells regain agonist responsiveness as synthesis of RGS2 stops. Analyzing contraction of mesenteric resistance arteries supported the biological relevance of this mechanism. Because RGS2 mRNA expression often is strikingly and transiently up-regulated and then down-regulated upon cell stimulation, our findings indicate that proteolytic degradation tightly couples RGS2 transcription, protein levels, and function. Together these mechanisms provide tight temporal control of G q/11 -coupled receptor signaling in the cardiovascular, immune, and nervous systems. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Endothelial Mechanotransduction, Redox Signaling and the Regulation of Vascular Inflammatory Pathways

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    Shampa Chatterjee

    2018-06-01

    Full Text Available The endothelium that lines the interior of blood vessels is directly exposed to blood flow. The shear stress arising from blood flow is “sensed” by the endothelium and is “transduced” into biochemical signals that eventually control vascular tone and homeostasis. Sensing and transduction of physical forces occur via signaling processes whereby the forces associated with blood flow are “sensed” by a mechanotransduction machinery comprising of several endothelial cell elements. Endothelial “sensing” involves converting the physical cues into cellular signaling events such as altered membrane potential and activation of kinases, which are “transmission” signals that cause oxidant production. Oxidants produced are the “transducers” of the mechanical signals? What is the function of these oxidants/redox signals? Extensive data from various studies indicate that redox signals initiate inflammation signaling pathways which in turn can compromise vascular health. Thus, inflammation, a major response to infection or endotoxins, can also be initiated by the endothelium in response to various flow patterns ranging from aberrant flow to alteration of flow such as cessation or sudden increase in blood flow. Indeed, our work has shown that endothelial mechanotransduction signaling pathways participate in generation of redox signals that affect the oxidant and inflammation status of cells. Our goal in this review article is to summarize the endothelial mechanotransduction pathways that are activated with stop of blood flow and with aberrant flow patterns; in doing so we focus on the complex link between mechanical forces and inflammation on the endothelium. Since this “inflammation susceptible” phenotype is emerging as a trigger for pathologies ranging from atherosclerosis to rejection post-organ transplant, an understanding of the endothelial machinery that triggers these processes is very crucial and timely.

  15. Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology.

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    Marcela Montes de Oca

    2016-01-01

    Full Text Available Tumor necrosis factor (TNF is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1 cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.

  16. The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development.

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    Rob C M de Jong

    Full Text Available Genetic P300/CBP-associated factor (PCAF variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB-mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia.PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals.These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.

  17. Regulation of vascular endothelial growth factor expression by homeodomain-interacting protein kinase-2

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    D'Orazi Gabriella

    2008-07-01

    Full Text Available Abstract Background Homeodomain-interacting protein kinase-2 (HIPK2 plays an essential role in restraining tumor progression as it may regulate, by itself or within multiprotein complexes, many proteins (mainly transcription factors involved in cell growth and apoptosis. This study takes advantage of the recent finding that HIPK2 may repress the β-catenin transcription activity. Thus, we investigated whether HIPK2 overexpression may down-regulate vascular endothelial growth factor (VEGF levels (a β-catenin target gene and the role of β-catenin in this regulation, in order to consider HIPK2 as a tool for novel anti-tumoral therapeutical approaches. Methods The regulation of VEGF expression by HIPK2 was evaluated by using luciferase assay with VEGF reporter construct, after overexpression of the β-catenin transcription factor. Relative quantification of VEGF and β-catenin mRNAs were assessed by reverse-transcriptase-PCR (RT-PCR analyses, following HIPK2 overexpression, while β-catenin protein levels were evaluated by western immunoblotting. Results HIPK2 overexpression in tumor cells downregulated VEGF mRNA levels and VEGF promoter activity. The VEGF downregulation was partly depending on HIPK2-mediated β-catenin regulation. Thus, HIPK2 could induce β-catenin protein degradation that was prevented by cell treatment with proteasome inhibitor MG132. The β-catenin degradation was dependent on HIPK2 catalytic activity and independent of p53 and glycogen synthase kinase 3β (GSK-3β activities. Conclusion These results suggest that VEGF might be a target of HIPK2, at least in part, through regulation of β-catenin activity. These findings support the function of HIPK2 as tumor suppressor and hypothesise a role for HIPK2 as antiangiogenic tool in tumor therapy approaches.

  18. Nitric oxide and TNFα are critical regulators of reversible lymph node vascular remodeling and adaptive immune response.

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    Stephanie L Sellers

    Full Text Available Lymph node (LN vascular growth, at the level of the main arteriole, was recently characterized for the first time during infection. Arteriole diameter was shown to increase for at least seven days and to occur via a CD4(+ T cell dependent mechanism, with vascular expansion playing a critical role in regulating induction of adaptive immune response. Here, using intravital microscopy of the inguinal LN during herpes simplex type II (HSV-2 infection, the data provides the first studies that demonstrate arteriole expansion during infection is a reversible vascular event that occurs via eutrophic outward remodeling. Furthermore, using genetic ablation models, and pharmacological blockade, we reveal arteriole remodeling and LN hypertrophy to be dependent upon both endothelial nitric oxide synthase (eNOS and TNFα expression. Additionally, we reveal transient changes in nitric oxide (NO levels to be a notable feature of response to viral infection and LN vascular remodeling and provide evidence that mast cells are the critical source of TNFα required to drive arteriole remodeling. Overall, this study is the first to fully characterize LN arteriole vascular changes throughout the course of infection. It effectively reveals a novel role for NO and TNFα in LN cellularity and changes in LN vascularity, which represent key advances in understanding LN vascular physiology and adaptive immune response.

  19. Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.

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    Juan Rodríguez-Vita

    Full Text Available BACKGROUND: The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells. METHODOLOGY: In cultured vascular smooth muscle cells (VSMCs statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII, and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-beta/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected. CONCLUSIONS: Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs.

  20. A Unique Immunofluorescence Protocol to Detect Protein Expression in Vascular Tissues: Tacking a Long Standing Pathological Hitch

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    Puneet GANDHI

    2018-01-01

    Full Text Available Objective: Autofluorescence induced interference is one of the major drawbacks in immunofluorescence analysis of formalin-fixed paraffin-embedded tissues, as it decreases the signal-to-noise ratio of specific labeling. Apart from aldehyde-fixation induced artifacts; collagen and elastin, red blood cells and endogenous fluorescent pigment lipofuscin are prime sources of autofluorescence in vascular and aging tissues. We describe herein, an optimized indirect-immunofluorescence method for archival formalin-fixed paraffin-embedded tissues tissues and cryo sections, using a combination of 3-reagents in a specific order, to achieve optimal fluorescence signals and imaging. Material and Method: Human telomerase reverse transcriptase, a protein implicated as a proliferation marker, was chosen relevant to its expression in solid tumors along with 3 other intracellular proteins exhibiting nuclear and/or cytoplasmic expression. Staining was performed on 10 glioma tissue sections along with 5 of their cryo sections, 5 sections each of hepatocellular, lung, papillary-thyroid and renal cell carcinoma, with 10 non-malignant brain tissue samples serving as control. Specimens were imaged using epifluorescence microscopy, followed by software-based quantification of fluorescence signals for statistical analysis and validation. Results: We observed that the combined application of sodium-borohydride followed by crystal violet before antigen retrieval and a Sudan black B treatment after secondary antibody application proved to be most efficacious for masking autofluorescence/non-specific background in vascular tissues. Conclusion: This unique trio-methodology provides quantifiable observations with maximized fluorescence signal intensity of the target protein for longer retention time of the signal even after prolonged storage. The results can be extrapolated to other human tissues for different protein targets.

  1. Characterisation of the vascular pathology in Sigmodon hispidus (Rodentia: Cricetidae following experimental infection with Angiostrongylus costaricensis (Nematoda: Metastrongylidae

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    Danielle Ingrid Bezerra de Vasconcelos

    Full Text Available BACKGROUND Angiostrongylus costaricensis is a nematode that causes human abdominal angiostrongyliasis, a disease found mainly in Latin American countries and particularly in Brazil and Costa Rica. Its life cycle involves exploitation of both invertebrate and vertebrate hosts. Its natural reservoir is a vertebrate host, the cotton rat Sigmodon hispidus. The adult worms live in the ileo-colic branches of the upper mesenteric artery of S. hispidus, causing periarteritis. However, there is a lack of data on the development of vasculitis in the course of infection. OBJECTIVE To describe the histopathology of vascular lesions in S. hispidus following infection with A. costaricensis. METHODS Twenty-one S. hispidus were euthanised at 30, 50, 90 and 114 days post-infection (dpi, and guts and mesentery (including the cecal artery were collected. Tissues were fixed in Carson’s Millonig formalin, histologically processed for paraffin embedding, sectioned with a rotary microtome, and stained with hematoxylin-eosin, resorcin-fuchsin, Perls, Sirius Red (pH = 10.2, Congo Red, and Azan trichrome for brightfield microscopy analysis. FINDINGS At 30 and 50 dpi, live eggs and larvae were present inside the vasa vasorum of the cecal artery, leading to eosinophil infiltrates throughout the vessel adventitia and promoting centripetal vasculitis with disruption of the elastic layers. Disease severity increased at 90 and 114 dpi, when many worms had died and the intensity of the vascular lesions was greatest, with intimal alterations, thrombus formation, iron accumulation, and atherosclerosis. CONCLUSION In addition to abdominal angiostrongyliasis, our data suggest that this model could be very useful for autoimune vasculitis and atherosclerosis studies.

  2. Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer.

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    Roberts, David D; Kaur, Sukhbir; Isenberg, Jeffrey S

    2017-10-20

    In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

  3. DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses.

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    Bruneau, Sarah; Nakayama, Hironao; Woda, Craig B; Flynn, Evelyn A; Briscoe, David M

    2013-09-05

    The maintenance of normal tissue homeostasis and the prevention of chronic inflammatory disease are dependent on the active process of inflammation resolution. In endothelial cells (ECs), proinflammation results from the activation of intracellular signaling responses and/or the inhibition of endogenous regulatory/pro-resolution signaling networks that, to date, are poorly defined. In this study, we find that DEP domain containing mTOR interacting protein (DEPTOR) is expressed in different microvascular ECs in vitro and in vivo, and using a small interfering RNA (siRNA) knockdown approach, we find that it regulates mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 1 activation in part through independent mechanisms. Moreover, using limited gene arrays, we observed that DEPTOR regulates EC activation including mRNA expression of the T-cell chemoattractant chemokines CXCL9, CXCL10, CXCL11, CX3CL1, CCL5, and CCL20 and the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (P < .05). DEPTOR siRNA-transfected ECs also bound increased numbers of peripheral blood mononuclear cells (P < .005) and CD3+ T cells (P < .005) in adhesion assays in vitro and had increased migration and angiogenic responses in spheroid sprouting (P < .01) and wound healing (P < .01) assays. Collectively, these findings define DEPTOR as a critical upstream regulator of EC activation responses and suggest that it plays an important role in endogenous mechanisms of anti-inflammation and pro-resolution.

  4. Modulation of CaV1.2 calcium channel by neuropeptide W regulates vascular myogenic tone via G protein-coupled receptor 7.

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    Ji, Li; Zhu, Huayuan; Chen, Hong; Fan, Wenyong; Chen, Junjie; Chen, Jing; Zhu, Guoqing; Wang, Juejin

    2015-12-01

    Neuropeptide W (NPW), an endogenous ligand for the G protein-coupled receptor 7 (GPR7), was first found to make important roles in central nerve system. In periphery, NPW was also present and regulated intracellular calcium homeostasis by L-type calcium channels. This study was designed to discover the effects of NPW-GPR7 on the function of CaV1.2 calcium channels in the vascular smooth muscle cells (VSMCs) and vasotone of arterial vessels. By whole-cell patch clamp, we studied the effects of NPW-23, the active form of NPW, on the CaV1.2 channels in the heterologously transfected human embryonic kidney 293 cells and VSMCs isolated from rat. Living system was used to explore the physiological function of NPW-23 in arterial myogenic tone. To investigate the pathological relevance, NPW mRNA level of mesenteric arteries was measured in the hypertensive and normotensive rats. NPW's receptor GPR7 was coexpressed with CaV1.2 channels in arterial smooth muscle. NPW-23 increased the ICa,L in transfected human embryonic kidney 293 cells and VSMCs via GPR7, which could be abrogated by phospholipase C (PLC)/protein kinase C (PKC) inhibitors, not protein kinase A or protein kinase G inhibitor. After NPW-23 application, the expression of pan phospho-PKC was increased; moreover, intracellular diacylglycerol level, the second messenger catalyzed by PLC, was increased 1.5-2-fold. Application with NPW-23 increased pressure-induced vasotone of the rat mesenteric arteries. Importantly, the expression of NPW was decreased in the hypertensive rats. NPW-23 regulates ICa,L via GPR7, which is mediated by PLC/PKC signaling, and such a mechanism plays a role in modulating vascular myogenic tone, which may involve in the development of vascular hypertension.

  5. Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model.

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    Astrid Menning

    Full Text Available Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlying pathogenesis of menstrual disorders remain poorly investigated up to date. Among others, this is based on a lack of appropriate pre-clinical animal models. We here employ a mouse menstruation model induced by priming mice with gonadal hormones and application of a physical stimulus into the uterus followed by progesterone removal. As in women, these events are accompanied by menstrual-like bleeding and tissue remodeling processes, i.e. disintegration of decidualized endometrium, as well as subsequent repair. We demonstrate that the onset of bleeding coincides with strong upregulation of inflammatory mediators and massive granulocyte influx into the uterus. Uterine granulocytes play a central role in regulating local tissue remodeling since depletion of these cells results in dysregulated expression of matrix modifying enzymes. As described here for the first time, uterine blood loss can be quantified by help of tampon-like cotton pads. Using this novel technique, we reveal that blood loss is strongly reduced upon inhibition of endometrial vascularization and thus, is a key regulator of menstrual bleeding. Taken together, we here identify angiogenesis and infiltrating granulocytes as critical determinants of uterine bleeding and tissue remodeling in a mouse menstruation model. Importantly, our study provides a technical and scientific basis allowing quantification of uterine blood loss in mice and thus, assessment of therapeutic intervention, proving great potential for future use in basic research and drug discovery.

  6. The adapter protein, Grb10, is a positive regulator of vascular endothelial growth factor signaling.

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    Giorgetti-Peraldi, S; Murdaca, J; Mas, J C; Van Obberghen, E

    2001-07-05

    Vascular endothelial growth factor (VEGF) is an important regulator of vasculogenesis and angiogenesis. Activation of VEGF receptors leads to the recruitment of SH2 containing proteins which link the receptors to the activation of signaling pathways. Here we report that Grb10, an adapter protein of which the biological role remains unknown, is tyrosine phosphorylated in response to VEGF in endothelial cells (HUVEC) and in 293 cells expressing the VEGF receptor KDR. An intact SH2 domain is required for Grb10 tyrosine phosphorylation in response to VEGF, and this phosphorylation is mediated in part through the activation of Src. In HUVEC, VEGF increases Grb10 mRNA level. Expression of Grb10 in HUVEC or in KDR expressing 293 cells results in an increase in the amount and in the tyrosine phosphorylation of KDR. In 293 cells, this is correlated with the activation of signaling molecules, such as MAP kinase. By expressing mutants of Grb10, we found that the positive action of Grb10 is independent of its SH2 domain. Moreover, these Grb10 effects on KDR seem to be specific since Grb10 has no effect on the insulin receptor, and Grb2, another adapter protein, does not mimic the effect of Grb10 on KDR. In conclusion, we propose that VEGF up-regulates Grb10 level, which in turn increases KDR molecules, suggesting that Grb10 could be involved in a positive feedback loop in VEGF signaling.

  7. Down-regulation of endothelin binding sites in rat vascular smooth muscle cells

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    Roubert, P.; Gillard, V.; Plas, P.; Chabrier, P.E.; Braquet, P.

    1990-01-01

    In cultured rat aortic smooth muscle cells, [ 125 I]endothelin (ET-1) bound to an apparent single class of high affinity recognition sites with a dissociation constant of 1.84 +/- 0.29 nmol/L and a maximum binding of 62 +/- 10.5 fmol/10(6) cells. The binding was not affected by calcium antagonists or vasoactive substances, including angiotensin II, arginine vasopressin, atrial natriuretic factor and bradykinin. Exposure of the cells to ET-1 (0.01 nmol/L to 10 nmol/L) resulted in an apparent dose-dependent reduction of the number of endothelin binding sites with no significant modification of its binding affinity. The time course of the down-regulation of ET-1 binding sites showed that this effect was present after 30 min incubation and persisted after 18 h. This indicates that down-regulation of ET-1 binding sites can modulate the activity of ET-1 and suggests a rapid internalization of ET-1 in vascular cells

  8. Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.

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    Jingshan Zhao

    Full Text Available The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL, a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF signaling and angiogenesis in endothelial cells (ECs. We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.

  9. Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells.

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    Feaver, Ryan E; Gelfand, Bradley D; Blackman, Brett R

    2013-01-01

    Haemodynamic variations are inherent to blood vessel geometries (such as bifurcations) and correlate with regional development of inflammation and atherosclerosis. However, the complex frequency spectrum characteristics from these haemodynamics have never been exploited to test whether frequency variations are critical determinants of endothelial inflammatory phenotype. Here we utilize an experimental Fourier transform analysis to systematically manipulate individual frequency harmonics from human carotid shear stress waveforms applied in vitro to human endothelial cells. The frequency spectrum, specifically the 0 th and 1st harmonics, is a significant regulator of inflammation, including NF-κB activity and downstream inflammatory phenotype. Further, a harmonic-based regression-model predicts eccentric NF-κB activity observed in the human internal carotid artery. Finally, short interfering RNA-knockdown of the mechanosensor PECAM-1 reverses frequency-dependent regulation of NF-κB activity. Thus, PECAM-1 may have a critical role in the endothelium's exquisite sensitivity to complex shear stress frequency harmonics and provide a mechanism for the focal development of vascular inflammation.

  10. NONOates regulate KCl cotransporter-1 and -3 mRNA expression in vascular smooth muscle cells.

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    Di Fulvio, Mauricio; Lauf, Peter K; Shah, Shalin; Adragna, Norma C

    2003-05-01

    Nitric oxide (NO) donors regulate KCl cotransport (KCC) activity and cotransporter-1 and -3 (KCC1 and KCC3) mRNA expression in sheep erythrocytes and in primary cultures of rat vascular smooth muscle cells (VSMCs), respectively. In this study, we used NONOates as rapid and slow NO releasers to provide direct evidence implicating NO as a regulator of KCC3 gene expression at the mRNA level. In addition, we used the expression of KCC3 mRNA to further investigate the mechanism of action of these NO donors at the cellular level. Treatment of VSMCs with rapid NO releasers, like NOC-5 and NOC-9, as well as with the direct NO-independent soluble guanylyl cyclase (sGC) stimulator YC-1, acutely increased KCC3 mRNA expression in a concentration- and time-dependent manner. The slow NO releaser NOC-18 had no effect on KCC3 gene expression. A specific NO scavenger completely prevented the NONOate-induced KCC3 mRNA expression. Inhibition of sGC with LY-83583 blocked the NONOate- and YC-1-induced KCC3 mRNA expression. This study shows that in primary cultures of rat VSMCs, the fast NO releasers NOC-9 and NOC-5, but not the slow NO releaser NOC-18, acutely upregulate KCC3 mRNA expression in a NO/sGC-dependent manner.

  11. Sphingosine-1-phosphate regulates RGS2 and RGS16 mRNA expression in vascular smooth muscle cells

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    Hendriks-Balk, Mariëlle C.; Hajji, Najat; van Loenen, Pieter B.; Michel, Martin C.; Peters, Stephan L. M.; Alewijnse, Astrid E.

    2009-01-01

    Regulator of G protein signalling (RGS) protein expression is altered under growth promoting conditions in vascular smooth muscle cells (VSMCs). Since sphingosine-1-phosphate (S1P) is an important growth stimulatory factor, we investigated whether stimulation of VSMCs with S1P results in alterations

  12. Segmentation of white matter hyperintensities using convolutional neural networks with global spatial information in routine clinical brain MRI with none or mild vascular pathology.

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    Rachmadi, Muhammad Febrian; Valdés-Hernández, Maria Del C; Agan, Maria Leonora Fatimah; Di Perri, Carol; Komura, Taku

    2018-06-01

    We propose an adaptation of a convolutional neural network (CNN) scheme proposed for segmenting brain lesions with considerable mass-effect, to segment white matter hyperintensities (WMH) characteristic of brains with none or mild vascular pathology in routine clinical brain magnetic resonance images (MRI). This is a rather difficult segmentation problem because of the small area (i.e., volume) of the WMH and their similarity to non-pathological brain tissue. We investigate the effectiveness of the 2D CNN scheme by comparing its performance against those obtained from another deep learning approach: Deep Boltzmann Machine (DBM), two conventional machine learning approaches: Support Vector Machine (SVM) and Random Forest (RF), and a public toolbox: Lesion Segmentation Tool (LST), all reported to be useful for segmenting WMH in MRI. We also introduce a way to incorporate spatial information in convolution level of CNN for WMH segmentation named global spatial information (GSI). Analysis of covariance corroborated known associations between WMH progression, as assessed by all methods evaluated, and demographic and clinical data. Deep learning algorithms outperform conventional machine learning algorithms by excluding MRI artefacts and pathologies that appear similar to WMH. Our proposed approach of incorporating GSI also successfully helped CNN to achieve better automatic WMH segmentation regardless of network's settings tested. The mean Dice Similarity Coefficient (DSC) values for LST-LGA, SVM, RF, DBM, CNN and CNN-GSI were 0.2963, 0.1194, 0.1633, 0.3264, 0.5359 and 5389 respectively. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

  13. MicroRNA-147b regulates vascular endothelial barrier function by targeting ADAM15 expression.

    Directory of Open Access Journals (Sweden)

    Victor Chatterjee

    Full Text Available A disintegrin and metalloproteinase15 (ADAM15 has been shown to be upregulated and mediate endothelial hyperpermeability during inflammation and sepsis. This molecule contains multiple functional domains with the ability to modulate diverse cellular processes including cell adhesion, extracellular matrix degradation, and ectodomain shedding of transmembrane proteins. These characteristics make ADAM15 an attractive therapeutic target in various diseases. The lack of pharmacological inhibitors specific to ADAM15 prompted our efforts to identify biological or molecular tools to alter its expression for further studying its function and therapeutic implications. The goal of this study was to determine if ADAM15-targeting microRNAs altered ADAM15-induced endothelial barrier dysfunction during septic challenge by bacterial lipopolysaccharide (LPS. An in silico analysis followed by luciferase reporter assay in human vascular endothelial cells identified miR-147b with the ability to target the 3' UTR of ADAM15. Transfection with a miR-147b mimic led to decreased total, as well as cell surface expression of ADAM15 in endothelial cells, while miR-147b antagomir produced an opposite effect. Functionally, LPS-induced endothelial barrier dysfunction, evidenced by a reduction in transendothelial electric resistance and increase in albumin flux across endothelial monolayers, was attenuated in cells treated with miR-147b mimics. In contrast, miR-147b antagomir exerted a permeability-increasing effect in vascular endothelial cells similar to that caused by LPS. Taken together, these data suggest the potential role of miR147b in regulating endothelial barrier function by targeting ADAM15 expression.

  14. Hsc70 regulates cell surface ASIC2 expression and vascular smooth muscle cell migration.

    Science.gov (United States)

    Grifoni, Samira C; McKey, Susan E; Drummond, Heather A

    2008-05-01

    Recent studies suggest members of the degenerin (DEG)/epithelial Na(+) channel (ENaC)/acid-sensing ion channel (ASIC) protein family play an important role in vascular smooth muscle cell (VSMC) migration. In a previous investigation, we found suppression of a certain DEG/ENaC/ASIC member, ASIC2, increased VSMC chemotactic migration, raising the possibility that ASIC2 may play an inhibitory role. Because ASIC2 protein was retained in the cytoplasm, we reasoned increasing surface expression of ASIC2 might unmask the inhibitory role of ASIC2 in VSMC migration so we could test the hypothesis that ASIC2 inhibits VSMC migration. Therefore, we used the chemical chaperone glycerol to enhance ASIC2 expression. Glycerol 1) increased cytoplasm ASIC2 expression, 2) permitted detection of ASIC2 at the cell surface, and 3) inhibited platelet-derived growth factor (PDGF)-bb mediated VSMC migration. Furthermore, ASIC2 silencing completely abolished the inhibitory effect of glycerol on migration, suggesting upregulation of ASIC2 is responsible for glycerol-induced inhibition of VSMC migration. Because other investigators have shown that glycerol regulates ENaC/ASIC via interactions with a certain heat shock protein, heat shock protein 70 (Hsc70), we wanted to determine the importance of Hsc70 on ASIC2 expression in VSMCs. We found that Hsc70 silencing increases ASIC2 cell surface expression and inhibits VSMC migration, which is abolished by cosilencing ASIC2. These data demonstrate that Hsc70 inhibits ASIC2 expression, and, when the inhibitory effect of Hsc70 is removed, ASIC2 expression increases, resulting in reduced VSMC migration. Because VSMC migration contributes to vasculogenesis and remodeling following vascular injury, our findings raise the possibility that ASIC2-Hsc70 interactions may play a role in these processes.

  15. Platelet-derived growth factor regulates K-Cl cotransport in vascular smooth muscle cells.

    Science.gov (United States)

    Zhang, Jing; Lauf, Peter K; Adragna, Norma C

    2003-03-01

    Platelet-derived growth factor (PDGF), a potent serum mitogen for vascular smooth muscle cells (VSMCs), plays an important role in membrane transport regulation and in atherosclerosis. K-Cl cotransport (K-Cl COT/KCC), the coupled-movement of K and Cl, is involved in ion homeostasis. VSMCs possess K-Cl COT activity and the KCC1 and KCC3 isoforms. Here, we report on the effect of PDGF on K-Cl COT activity and mRNA expression in primary cultures of rat VSMCs. K-Cl COT was determined as the Cl-dependent Rb influx and mRNA expression by semiquantitative RT-PCR. Twenty four-hour serum deprivation inhibited basal K-Cl COT activity. Addition of PDGF increased total protein content and K-Cl COT activity in a time-dependent manner. PDGF activated K-Cl COT in a dose-dependent manner, both acutely (10 min) and chronically (12 h). AG-1296, a selective inhibitor of the PDGF receptor tyrosine kinase, abolished these effects. Actinomycin D and cycloheximide had no effect on the acute PDGF activation of K-Cl COT, suggesting posttranslational regulation by the drug. Furthermore, PDGF increased KCC1 and decreased KCC3 mRNA expression in a time-dependent manner. These results indicate that chronic activation of K-Cl COT activity by PDGF may involve regulation of the two KCC mRNA isoforms, with KCC1 playing a dominant role in the mechanism of PDGF-mediated activation.

  16. Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

    Directory of Open Access Journals (Sweden)

    Heather A. Himburg

    2012-10-01

    Full Text Available The mechanisms through which the bone marrow (BM microenvironment regulates hematopoietic stem cell (HSC fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

  17. Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters.

    Science.gov (United States)

    Ververis, J J; Ku, L; Delafontaine, P

    1993-06-01

    Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells. To characterize regulation of vascular IGF I receptors, we performed radioligand displacement experiments using rat aortic smooth muscle cells (RASMs). Serum deprivation for 48 hours caused a 40% decrease in IGF I receptor number. Exposure of quiescent RASMs to platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or angiotensin II (Ang II) caused a 1.5-2.0-fold increase in IGF I receptors per cell. After FGF exposure, there was a marked increase in the mitogenic response to IGF I. IGF I downregulated its receptors in the presence of platelet-poor plasma. Stimulation of protein kinase C (PKC) by exposure of quiescent RASMs to phorbol 12-myristate 13-acetate caused a biphasic response in IGF I binding; there was a 42% decrease in receptor number at 45 minutes and a 238% increase at 24 hours. To determine the role of PKC in growth factor-induced regulation of IGF I receptors, we downregulated PKC by exposing RASMs to phorbol 12,13-dibutyrate (PDBu) for 48 hours. PDGF- and FGF- but not Ang II-mediated upregulation of IGF I receptors was completely inhibited in PDBu-treated cells. Thus, acute PKC activation by phorbol esters inhibits IGF I binding, whereas chronic PKC activation increases IGF I binding. PDGF and FGF but not Ang II regulate vascular IGF I receptors through a PKC-dependent pathway. These data provide new insights into the regulation of vascular smooth muscle cell IGF I receptors in vitro and are of potential importance in characterizing vascular proliferative responses in vivo.

  18. Effect of Aggression Regulation on Eating Disorder Pathology : RCT of a Brief Body and Movement Oriented Intervention

    NARCIS (Netherlands)

    Boerhout, Cees; Swart, Marte; Van Busschbach, Jooske T.; Hoek, Hans W.

    ObjectiveThe objective of the study is to evaluate the effect of a brief body and movement oriented intervention on aggression regulation and eating disorder pathology for individuals with eating disorders. MethodIn a first randomized controlled trial, 40 women were allocated to either the

  19. Regulation by basic fibroblast growth factor of glycosaminoglycan biosynthesis in cultured vascular endothelial cells.

    Science.gov (United States)

    Kaji, T; Hiraga, S; Ohkawara, S; Inada, M; Yamamoto, C; Kozuka, H; Koizumi, F

    1995-05-01

    The alteration of glycosaminoglycans (GAGs) in cultured bovine aortic endothelial cells after exposure to basic fibroblast growth factor (bFGF) was investigated. It was found that the incorporation of [3H]glucosamine into GAGs was markedly increased by bFGF in both the cell layer and the conditioned medium; however, that of [35S]sulfate was not changed by the growth factor. These results indicated that bFGF enhanced the sugar-chain formation but did not affect their sulfation in endothelial GAG production. Similar changes were observed in either bovine aortic smooth-muscle cells and human fibroblastic IMR-90 cells to greater and lesser degrees, respectively. Characterization of GAGs in the endothelial cell layer and the conditioned medium revealed that bFGF enhanced both heparan sulfate and the other GAGs to a similar degree. The present data suggest that bFGF may be involved in the regulation of the blood coagulation system via altering GAGs of the vascular tissue when the endothelium was damaged.

  20. CD147 induces up-regulation of vascular endothelial growth factor in U937-derived foam cells through PI3K/AKT pathway.

    Science.gov (United States)

    Zong, JiaXin; Li, YunTian; Du, DaYong; Liu, Yang; Yin, YongJun

    2016-11-01

    Intraplaque angiogenesis has been recognized as an important risk factor for the rupture of advanced atherosclerotic plaques in recent years. CD147, also called Extracellular Matrix Metalloproteinase Inducer, has been found the ability to promote angiogenesis in many pathological conditions such as cancer diseases and rheumatoid arthritis via the up-regulation of vascular endothelial growth factor (VEGF), a critical mediator of angiogenesis. We investigated whether CD147 would also induce the up-regulation of VEGF in the foam cells formation process and explored the probable signaling pathway. The results showed the expression of CD147 and VEGF was significantly higher in U937-derived foam cells. After CD147 stealth siRNA transfection treatment, the production of VEGF was reduced depended on the inhibition efficiency of CD147 siRNAs.The special signaling pathway inhibitors LY294002, SP600125, SB203580 and U0126 were added to cultures respectively and the results showed LY294002 dose-dependently inhibited the expression of VEGF. The reduction of phospho-Akt was observed in both LY294002 and siRNA groups, suggested that the phosphatidylinositol 3-kinase/Akt pathway may be the probable signaling pathway underlying CD147 induced up-regulation of VEGF in U937-derived foam cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNFα-mediated vascular smooth muscle cell proliferation via suppressing ERK activation

    International Nuclear Information System (INIS)

    Ichikawa, Tomonaga; Li, Jinqing; Dong, Xiaoyu; Potts, Jay D.; Tang, Dong-Qi; Li, Dong-Sheng; Cui, Taixing

    2010-01-01

    Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNFα)-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNFα-induced activation of ERK and DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNFα hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.

  2. Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells.

    Science.gov (United States)

    Qin, Qing; Chen, Ming; Yi, Bing; You, Xiaohua; Yang, Ping; Sun, Jianxin

    2014-12-01

    Endothelin-1 (ET-1) produced by vascular endothelial cells plays essential roles in the regulation of vascular tone and development of cardiovascular diseases. The objective of this study is to identify novel regulators implicated in the regulation of ET-1 expression in vascular endothelial cells (ECs). By using quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), we show that either ectopic expression of orphan nuclear receptor Nur77 or pharmacological activation of Nur77 by 6-mercaptopurine (6-MP) substantially inhibits ET-1 expression in human umbilical vein endothelial cells (HUVECs), under both basal and thrombin-stimulated conditions. Furthermore, thrombin-stimulated ET expression is significantly augmented in both Nur77 knockdown ECs and aort from Nur77 knockout mice, suggesting that Nur77 is a negative regulator of ET-1 expression. Inhibition of ET-1 expression by Nur77 occurs at gene transcriptional levels, since Nur77 potently inhibits ET-1 promoter activity, without affecting ET-1 mRNA stability. As shown in electrophoretic mobility shift assay (EMSA), Nur77 overexpression markedly inhibits both basal and thrombin-stimulated transcriptional activity of AP-1. Mechanistically, we demonstrate that Nur77 specially interacts with c-Jun and inhibits AP-1 dependent c-Jun promoter activity, which leads to a decreased expression of c-Jun, a critical component involved in both AP-1 transcriptional activity and ET-1 expression in ECs. These findings demonstrate that Nur77 is a novel negative regulator of ET-1 expression in vascular ECs through an inhibitory interaction with the c-Jun/AP-1 pathway. Activation of Nur77 may represent a useful therapeutic strategy for preventing certain cardiovascular diseases, such as atherosclerosis and pulmonary artery hypertension. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Endothelium derived nitric oxide synthase negatively regulates the PDGF-survivin pathway during flow-dependent vascular remodeling.

    Directory of Open Access Journals (Sweden)

    Jun Yu

    Full Text Available Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known. Here we show that abnormal flow-dependent remodeling in eNOS knockout mice (eNOS (-/- is associated with activation of the platelet derived growth factor (PDGF signaling pathway leading to the induction of the inhibitor of apoptosis, survivin. Interfering with PDGF signaling or survivin function corrects the abnormal remodeling seen in eNOS (-/- mice. Moreover, nitric oxide (NO negatively regulates PDGF driven survivin expression and cellular proliferation in cultured vascular smooth muscle cells. Collectively, our data suggests that eNOS negatively regulates the PDGF-survivin axis to maintain proportional flow-dependent luminal remodeling and vascular quiescence.

  4. Vascular development of the grapevine (Vitis vinifera L.) inflorescence rachis in response to flower number, plant growth regulators and defoliation.

    Science.gov (United States)

    Gourieroux, Aude M; Holzapfel, Bruno P; McCully, Margaret E; Scollary, Geoffrey R; Rogiers, Suzy Y

    2017-09-01

    The grapevine inflorescence is a determinate panicle and as buds emerge, shoot, flower and rachis development occur simultaneously. The growth and architecture of the rachis is determined by genetic and environmental factors but here we examined the role of flower and leaf number as well as hormones on its elongation and vascular development. The consequences of rachis morphology and vascular area on berry size and composition were also assessed. One week prior to anthesis, Merlot and Cabernet Sauvignon field vines were exposed to manual flower removal, exogenous plant growth regulators or pre-bloom leaf removal. Manual removal of half the flowers along the vertical axis of the inflorescence resulted in a shorter rachis in both cultivars. Conversely, inflorescences treated with gibberellic acid (GA 3 ) and the synthetic cytokinin, 6-benzylaminopurine (BAP) resulted in a longer rachis while pre-bloom removal of all leaves on the inflorescence-bearing shoot did not alter rachis length relative to untreated inflorescences. Across the treatments, the cross-sectional areas of the conducting xylem and phloem in the rachis were positively correlated to rachis girth, flower number at anthesis, bunch berry number, bunch berry fresh mass and bunch sugar content at harvest. Conversely, average berry size and sugar content were not linked to rachis vascular area. These data indicate that the morphological and vascular development of the rachis was more responsive to flower number and plant growth regulators than to leaf removal.

  5. Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibitor delivery in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Christian Schmidt-Lauber

    Full Text Available BACKGROUND: Tyrosine kinase inhibitors (TKIs are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF. Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important

  6. Inhibition of Extracellular Signal-Regulated Kinases Ameliorates Hypertension-Induced Renal Vascular Remodeling in Rat Models

    Directory of Open Access Journals (Sweden)

    Li Jing

    2011-11-01

    Full Text Available The aim of this study is to investigate the effect of the extracellular signal-regulated kinases 1/2 (ERK1/2 inhibitor, PD98059, on high blood pressure and related vascular changes. Blood pressure was recorded, thicknesses of renal small artery walls were measured and ERK1/2 immunoreactivity and erk2 mRNA in renal vascular smooth muscle cells (VSMCs and endothelial cells were detected by immunohistochemistry and in situ hybridization in normotensive wistar kyoto (WKY rats, spontaneously hypertensive rats (SHR and PD98059-treated SHR. Compared with normo-tensive WKY rats, SHR developed hypertension at 8 weeks of age, thickened renal small artery wall and asymmetric arrangement of VSMCs at 16 and 24 weeks of age. Phospho-ERK1/2 immunoreactivity and erk2 mRNA expression levels were increased in VSMCs and endothelial cells of the renal small arteries in the SHR. Treating SHR with PD98059 reduced the spontaneous hypertension-induced vascular wall thickening. This effect was associated with suppressions of erk2 mRNA expression and ERK1/2 phosphorylation in VSMCs and endothelial cells of the renal small arteries. It is concluded that inhibition of ERK1/2 ameliorates hypertension induced vascular remodeling in renal small arteries.

  7. Effect of Aggression Regulation on Eating Disorder Pathology: RCT of a Brief Body and Movement Oriented Intervention.

    Science.gov (United States)

    Boerhout, Cees; Swart, Marte; Van Busschbach, Jooske T; Hoek, Hans W

    2016-03-01

    The objective of the study is to evaluate the effect of a brief body and movement oriented intervention on aggression regulation and eating disorder pathology for individuals with eating disorders. In a first randomized controlled trial, 40 women were allocated to either the aggression regulation intervention plus supportive contact or a control condition of supportive contact only. The intervention was delivered by a psychomotor therapist. Participants completed questionnaires on anger coping and eating disorder pathology. Independent samples t-tests were performed on the difference between pre-treatment and post-treatment scores. Twenty-nine participants completed questionnaires at pre-intervention and post-intervention. The intervention resulted in a significantly greater improvement of anger coping, as well as of eating disorder pathology. Results indicate that body and movement-oriented aggression regulation may be a viable add-on for treating eating disorders. It tackles a difficult to treat emotion which may have a role in blocking the entire process of treating eating disorders. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

  8. Endogenous Vascular Endothelial Growth Factor-A (VEGF-A) Maintains Endothelial Cell Homeostasis by Regulating VEGF Receptor-2 Transcription*

    Science.gov (United States)

    E, Guangqi; Cao, Ying; Bhattacharya, Santanu; Dutta, Shamit; Wang, Enfeng; Mukhopadhyay, Debabrata

    2012-01-01

    Vascular endothelial growth factor A (VEGF-A) is one of the most important factors controlling angiogenesis. Although the functions of exogenous VEGF-A have been widely studied, the roles of endogenous VEGF-A remain unclear. Here we focused on the mechanistic functions of endogenous VEGF-A in endothelial cells. We found that it is complexed with VEGF receptor 2 (VEGFR-2) and maintains a basal expression level for VEGFR-2 and its downstream signaling activation. Endogenous VEGF-A also controls expression of key endothelial specific genes including VEGFR-2, Tie-2, and vascular endothelial cadherin. Of importance, endogenous VEGF-A differs from exogenous VEGF-A by regulating VEGFR-2 transcription through mediation of FoxC2 binding to the FOX:ETS motif, and the complex formed by endogenous VEGF-A with VEGFR-2 is localized within the EEA1 (early endosome antigen 1) endosomal compartment. Taken together, our results emphasize the importance of endogenous VEGF-A in endothelial cells by regulating key vascular proteins and maintaining the endothelial homeostasis. PMID:22167188

  9. Proline-rich tyrosine kinase 2 (Pyk2) mediates vascular endothelial-cadherin-based cell-cell adhesion by regulating beta-catenin tyrosine phosphorylation

    NARCIS (Netherlands)

    van Buul, Jaap D.; Anthony, Eloise C.; Fernandez-Borja, Mar; Burridge, Keith; Hordijk, Peter L.

    2005-01-01

    Vascular endothelial-cadherin (VE-cadherin) controls endothelial cell-cell adhesion and preserves endothelial integrity. In order to maintain endothelial barrier function, VE-cadherin function is tightly regulated through mechanisms that involve protein phosphorylation and cytoskeletal dynamics.

  10. Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Qiu [Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Wei, Bin [Department of Dermatology, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Zhao, Yu; Wang, Xuehu; Fu, Qining; Liu, Hong [Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China); Li, Fenghe, E-mail: lfh_cmu@126.com [Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China)

    2016-07-01

    Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRβ/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up-regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Krüppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. - Highlights: • Shh as a downstream effector of PDGF participates in PDGF-induced VSMC phenotypic modulation. • Shh can promote VSMC phenotypic switching from contractile to synthetic state. • Shh mediates VSMC phenotypic modulation through regulation of KLF4.

  11. Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

    International Nuclear Information System (INIS)

    Zeng, Qiu; Wei, Bin; Zhao, Yu; Wang, Xuehu; Fu, Qining; Liu, Hong; Li, Fenghe

    2016-01-01

    Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRβ/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up-regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Krüppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. - Highlights: • Shh as a downstream effector of PDGF participates in PDGF-induced VSMC phenotypic modulation. • Shh can promote VSMC phenotypic switching from contractile to synthetic state. • Shh mediates VSMC phenotypic modulation through regulation of KLF4.

  12. Glutathione regulation of redox-sensitive signals in tumor necrosis factor-α-induced vascular endothelial dysfunction

    International Nuclear Information System (INIS)

    Tsou, T.-C.; Yeh, S.C.; Tsai, F.-Y.; Chen, J.-W.; Chiang, H.-C.

    2007-01-01

    We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-α)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-α induces various biological effects on vascular cells, TNF-α dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-α concentrations, we adopted the lower TNF-α (0.2 ng/ml) to rule out the possible involvement of other TNF-α-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-α-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-α-induced nuclear factor-kappaB (NF-κB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-α. Inhibition of ERK, JNK, or NF-κB attenuates TNF-α-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-α induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-κB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-α. Although AP-1 activation by the lower TNF-α was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-α-induced adhesion molecule expression

  13. Regulation of plant vascular stem cells by endodermis-derived EPFL-family peptide hormones and phloem-expressed ERECTA-family receptor kinases.

    Science.gov (United States)

    Uchida, Naoyuki; Tasaka, Masao

    2013-12-01

    Plant vasculatures are complex tissues consisting of (pro)cambium, phloem, and xylem. The (pro)cambium serves as vascular stem cells that produce all vascular cells. The Arabidopsis ERECTA (ER) receptor kinase is known to regulate the architecture of inflorescence stems. It was recently reported that the er mutation enhances a vascular phenotype induced by a mutation of TDR/PXY, which plays a significant role in procambial proliferation, suggesting that ER participates in vascular development. However, detailed molecular mechanisms of the ER-dependent vascular regulation are largely unknown. Here, this work found that ER and its paralogue, ER-LIKE1, were redundantly involved in procambial development of inflorescence stems. Interestingly, their activity in the phloem was sufficient for vascular regulation. Furthermore, two endodermis-derived peptide hormones, EPFL4 and EPFL6, were redundantly involved in such regulation. It has been previously reported that EPFL4 and EPFL6 act as ligands of phloem-expressed ER for stem elongation. Therefore, these findings indicate that cell-cell communication between the endodermis and the phloem plays an important role in procambial development as well as stem elongation. Interestingly, similar EPFL-ER modules control two distinct developmental events by slightly changing their components: the EPFL4/6-ER module for stem elongation and the EPFL4/6-ER/ERL1 module for vascular development.

  14. Protein kinase A-alpha directly phosphorylates FoxO1 in vascular endothelial cells to regulate expression of vascular cellular adhesion molecule-1 mRNA.

    Science.gov (United States)

    Lee, Ji-Won; Chen, Hui; Pullikotil, Philomena; Quon, Michael J

    2011-02-25

    FoxO1, a forkhead box O class transcription factor, is abundant in insulin-responsive tissues. Akt, downstream from phosphatidylinositol 3-kinase in insulin signaling, phosphorylates FoxO1 at Thr(24), Ser(256), and Ser(319), negatively regulating its function. We previously reported that dehydroepiandrosterone-stimulated phosphorylation of FoxO1 in endothelial cells requires cAMP-dependent protein kinase α (PKA-α). Therefore, we hypothesized that FoxO1 is a novel direct substrate for PKA-α. Using an immune complex kinase assay with [γ-(32)P]ATP, purified PKA-α directly phosphorylated wild-type FoxO1 but not FoxO1-AAA (mutant with alanine substitutions at known Akt phosphorylation sites). Phosphorylation of wild-type FoxO1 (but not FoxO1-AAA) was detectable using phospho-specific antibodies. Similar results were obtained using purified GST-FoxO1 protein as the substrate. Thus, FoxO1 is a direct substrate for PKA-α in vitro. In bovine aortic endothelial cells, interaction between endogenous PKA-α and endogenous FoxO1 was detected by co-immunoprecipitation. In human aortic endothelial cells (HAEC), pretreatment with H89 (PKA inhibitor) or siRNA knockdown of PKA-α decreased forskolin- or prostaglandin E(2)-stimulated phosphorylation of FoxO1. In HAEC transfected with a FoxO-promoter luciferase reporter, co-expression of the catalytic domain of PKA-α, catalytically inactive mutant PKA-α, or siRNA against PKA-α caused corresponding increases or decreases in transactivation of the FoxO promoter. Expression of vascular cellular adhesion molecule-1 mRNA, up-regulated by FoxO1 in endothelial cells, was enhanced by siRNA knockdown of PKA-α or treatment of HAEC with the PKA inhibitor H89. Adhesion of monocytes to endothelial cells was enhanced by H89 treatment or overexpression of FoxO1-AAA, similar to effects of TNF-α treatment. We conclude that FoxO1 is a novel physiological substrate for PKA-α in vascular endothelial cells.

  15. Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials

    Science.gov (United States)

    Lee, Ted T.; García, José R.; Paez, Julieta I.; Singh, Ankur; Phelps, Edward A.; Weis, Simone; Shafiq, Zahid; Shekaran, Asha; Del Campo, Aránzazu; García, Andrés J.

    2015-03-01

    Materials engineered to elicit targeted cellular responses in regenerative medicine must display bioligands with precise spatial and temporal control. Although materials with temporally regulated presentation of bioadhesive ligands using external triggers, such as light and electric fields, have recently been realized for cells in culture, the impact of in vivo temporal ligand presentation on cell-material responses is unknown. Here, we present a general strategy to temporally and spatially control the in vivo presentation of bioligands using cell-adhesive peptides with a protecting group that can be easily removed via transdermal light exposure to render the peptide fully active. We demonstrate that non-invasive, transdermal time-regulated activation of cell-adhesive RGD peptide on implanted biomaterials regulates in vivo cell adhesion, inflammation, fibrous encapsulation, and vascularization of the material. This work shows that triggered in vivo presentation of bioligands can be harnessed to direct tissue reparative responses associated with implanted biomaterials.

  16. Crossing boundaries: a comprehensive survey of medical licensing laws and guidelines regulating the interstate practice of pathology.

    Science.gov (United States)

    Hiemenz, Matthew C; Leung, Stanley T; Park, Jason Y

    2014-03-01

    In the United States, recent judicial interpretation of interstate licensure laws has found pathologists guilty of malpractice and, more importantly, the criminal practice of medicine without a license. These judgments against pathologists highlight the need for a timely and comprehensive survey of licensure requirements and laws regulating the interstate practice of pathology. For all 50 states, each state medical practice act and state medical board website was reviewed. In addition, each medical board was directly contacted by electronic mail, telephone, or US registered mail for information regarding specific legislation or guidelines related to the interstate practice of pathology. On the basis of this information, states were grouped according to similarities in legislation and medical board regulations. This comprehensive survey has determined that states define the practice of pathology on the basis of the geographic location of the patient at the time of surgery or phlebotomy. The majority of states (n=32) and the District of Columbia allow for a physician with an out-of-state license to perform limited consultation to a physician with the specific state license. Several states (n=5) prohibit physicians from consultation without a license for the specific state. Overall, these results reveal the heterogeneity of licensure requirements between states. Pathologists who either practice in multiple states, send cases to out-of-state consultants, or serve as consultants themselves should familiarize themselves with the medical licensure laws of the states from which they receive or send cases.

  17. Na,K-ATPase regulates intercellular communication in the vascular wall via cSrc kinase dependent connexin43 phosphorylation

    DEFF Research Database (Denmark)

    Hangaard, Lise; Bouzinova, Elena; Stæhr, Christian Albeck

    2017-01-01

    Communication between vascular smooth muscle cells (VSMCs) is dependent on gap junctions and is regulated by the Na-K-ATPase. The Na-K-ATPase is therefore important for synchronized VSMC oscillatory activity, i.e., vasomotion. The signaling between the Na-K-ATPase and gap junctions is unknown. We...... coupling in rat mesenteric small arteries in vitro. Phosphorylation of cSrc kinase and connexin43 (Cx43) were semiquantified by Western blotting. Micromole concentration of ouabain reduced the amplitude of norepinephrine-induced vasomotion and desynchronized Ca2+ transients in VSMC in the arterial wall...

  18. Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells.

    Science.gov (United States)

    Ververis, J; Ku, L; Delafontaine, P

    1994-02-01

    Insulin-like growth factor I is an important mitogen for vascular smooth muscle cells, and its effects are regulated by several binding proteins. Western ligand blotting of conditioned medium from rat aortic smooth muscle cells detected a 24 kDa binding protein and a 28 kDa glycosylated variant of this protein, consistent with insulin-like growth factor binding protein-4 by size. Low amounts of a glycosylated 38 to 42 kDa doublet (consistent with binding protein-3) and a 31 kDa non-glycosylated protein also were present. Basic fibroblast growth factor markedly increased secretion of the 24 kDa binding protein and its 28 kDa glycosylated variant. This effect was dose- and time-dependent and was inhibited by co-incubation with cycloheximide. Crosslinking of [125I]-insulin-like growth factor I to cell monolayers revealed no surface-associated binding proteins, either basally or after agonist treatment. Induction of binding protein production by fibroblast growth factor at sites of vascular injury may be important in vascular proliferative responses in vivo.

  19. Vascular regulation of glioma stem-like cells: a balancing act.

    Science.gov (United States)

    Brooks, Lucy J; Parrinello, Simona

    2017-12-01

    Glioblastoma (GBM) are aggressive and therapy-resistant brain tumours driven by glioma stem-like cells (GSCs). GSC behaviour is controlled by the microenvironment, or niche, in which the cells reside. It is well-established that the vasculature is a key component of the GSC niche, which drives maintenance in the tumour bulk and invasion at the margin. Emerging evidence now indicates that the specific properties of the vasculature within these two regions impose different functional states on resident GSCs, generating distinct subpopulations. Here, we review these recent findings, focusing on the mechanisms that underlie GSC/vascular communication. We further discuss how plasticity enables GSCs to respond to vascular changes by interconverting bidirectionally between states, and address the therapeutic implications of this dynamic response. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Bone morphogenetic proteins regulate osteoprotegerin and its ligands in human vascular smooth muscle cells

    DEFF Research Database (Denmark)

    Knudsen, Kirsten Quyen Nguyen; Olesen, Ping; Ledet, Thomas

    2007-01-01

    The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved in the transformat......The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved...... in the transformation of human vascular smooth muscle cells (HVSMC) to osteoblast-like cells. In this study, we evaluated the effect of BMP-2, BMP-7 and transforming growth factor beta (TGF-beta1) on the secretion and mRNA expression of OPG and its ligands receptor activator of nuclear factor-kappabeta ligand (RANKL......) and TNF-related apoptosis-inducing ligand (TRAIL) in HVSMC. All three growth factors decreased OPG protein production significantly; these results were paralleled by reduced OPG mRNA expression. TRAIL mRNA levels were also decreased. RANKL mRNA expression declined when treated with TGF-beta1 but were...

  1. Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice

    Science.gov (United States)

    Manzini, S.; Pinna, C.; Busnelli, M.; Cinquanta, P.; Rigamonti, E.; Ganzetti, G.S.; Dellera, F.; Sala, A.; Calabresi, L.; Franceschini, G.; Parolini, C.; Chiesa, G.

    2015-01-01

    Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcatwt) and LCAT knockout (LcatKO) mice exposed to noradrenaline showed reduced contractility in LcatKO mice (P < 0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in LcatKO mice (P < 0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in LcatKO mouse aortas. Real-time PCR analysis indicated increased expression of β2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the β-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcatwt and LcatKO mice. The results indicate that LCAT deficiency leads to increased β2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity. PMID:26254103

  2. Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice.

    Science.gov (United States)

    Manzini, S; Pinna, C; Busnelli, M; Cinquanta, P; Rigamonti, E; Ganzetti, G S; Dellera, F; Sala, A; Calabresi, L; Franceschini, G; Parolini, C; Chiesa, G

    2015-11-01

    Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of β2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the β-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased β2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity. Copyright © 2015. Published by Elsevier Inc.

  3. Endotoxin-induced basal respiration alterations of renal HK-2 cells: A sign of pathologic metabolism down-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Quoilin, C., E-mail: cquoilin@ulg.ac.be [Laboratory of Biomedical Spectroscopy, Department of Physics, University of Liege, 4000 Liege (Belgium); Mouithys-Mickalad, A. [Center of Oxygen Research and Development, Department of Chemistry, University of Liege, 4000 Liege (Belgium); Duranteau, J. [Department of Anaesthesia and Surgical ICU, CHU Bicetre, University Paris XI Sud, 94275 Le Kremlin Bicetre (France); Gallez, B. [Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Universite catholique de Louvain, 1200 Brussels (Belgium); Hoebeke, M. [Laboratory of Biomedical Spectroscopy, Department of Physics, University of Liege, 4000 Liege (Belgium)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer A HK-2 cells model of inflammation-induced acute kidney injury. Black-Right-Pointing-Pointer Two oximetry methods: high resolution respirometry and ESR spectroscopy. Black-Right-Pointing-Pointer Oxygen consumption rates of renal cells decrease when treated with LPS. Black-Right-Pointing-Pointer Cells do not recover normal respiration when the LPS treatment is removed. Black-Right-Pointing-Pointer This basal respiration alteration is a sign of pathologic metabolism down-regulation. -- Abstract: To study the mechanism of oxygen regulation in inflammation-induced acute kidney injury, we investigate the effects of a bacterial endotoxin (lipopolysaccharide, LPS) on the basal respiration of proximal tubular epithelial cells (HK-2) both by high-resolution respirometry and electron spin resonance spectroscopy. These two complementary methods have shown that HK-2 cells exhibit a decreased oxygen consumption rate when treated with LPS. Surprisingly, this cellular respiration alteration persists even after the stress factor was removed. We suggested that this irreversible decrease in renal oxygen consumption after LPS challenge is related to a pathologic metabolic down-regulation such as a lack of oxygen utilization by cells.

  4. Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

    Science.gov (United States)

    Sparks, Matthew A; Stegbauer, Johannes; Chen, Daian; Gomez, Jose A; Griffiths, Robert C; Azad, Hooman A; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

    2015-12-01

    Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control. Copyright © 2015 by the American Society of Nephrology.

  5. DHEA attenuates PDGF-induced phenotypic proliferation of vascular smooth muscle A7r5 cells through redox regulation

    Energy Technology Data Exchange (ETDEWEB)

    Urata, Yoshishige; Goto, Shinji; Kawakatsu, Miho [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Yodoi, Junji [Department of Biological Responses, Institute for Viral Research, Graduate School of Medicine, Kyoto University, 53 Shogain, Kawahara-cho, Sakyo-ku, Kyoto 606-8397 (Japan); Eto, Masato [Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Akishita, Masahiro, E-mail: akishita-tky@umin.ac.jp [Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Kondo, Takahito [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2010-05-28

    It is known that dehydroepiandrosterone (DHEA) inhibits a phenotypic switch in vascular smooth muscle cells (VSMC) induced by platelet-derived growth factor (PDGF)-BB. However, the mechanism behind the effect of DHEA on VSMC is not clear. Previously we reported that low molecular weight-protein tyrosine phosphatase (LMW-PTP) dephosphorylates PDGF receptor (PDGFR)-{beta} via a redox-dependent mechanism involving glutathione (GSH)/glutaredoxin (GRX)1. Here we demonstrate that the redox regulation of PDGFR-{beta} is involved in the effect of DHEA on VSMC. DHEA suppressed the PDGF-BB-dependent phosphorylation of PDGFR-{beta}. As expected, DHEA increased the levels of GSH and GRX1, and the GSH/GRX1 system maintained the redox state of LMW-PTP. Down-regulation of the expression of LMW-PTP using siRNA restored the suppression of PDGFR-{beta}-phosphorylation by DHEA. A promoter analysis of GRX1 and {gamma}-glutamylcysteine synthetase ({gamma}-GCS), a rate-limiting enzyme of GSH synthesis, showed that DHEA up-regulated the transcriptional activity at the peroxisome proliferator-activated receptor (PPAR) response element, suggesting PPAR{alpha} plays a role in the induction of GRX1 and {gamma}-GCS expression by DHEA. In conclusion, the redox regulation of PDGFR-{beta} is involved in the suppressive effect of DHEA on VSMC proliferation through the up-regulation of GSH/GRX system.

  6. Regulation of vascular tone in rabbit ophthalmic artery: cross talk of endogenous and exogenous gas mediators.

    Science.gov (United States)

    Salomone, Salvatore; Foresti, Roberta; Villari, Ambra; Giurdanella, Giovanni; Drago, Filippo; Bucolo, Claudio

    2014-12-15

    Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) modulate vascular tone. In view of their therapeutic potential for ocular diseases, we examined the effect of exogenous CO and H2S on tone of isolated rabbit ophthalmic artery and their interaction with endogenous and exogenous NO. Ophthalmic artery segments mounted on a wire myograph were challenged with cumulative concentrations of phenylephrine (PE) in the presence or absence of NG-nitro-L-arginine (LNNA) to inhibit production of NO, the CO-releasing molecules CORMs or the H2S-donor GYY4137. The maximal vasoconstriction elicited by PE reached 20-30% of that induced by KCl but was dramatically increased by incubation with LNNA. GYY4137 significantly raised PE-mediated vasoconstriction, but it did not change the response to PE in the presence of LNNA or the relaxation to sodium nitroprusside (SNP). CORMs concentration-dependently inhibited PE-induced constriction, an effect that was synergistic with endogenous NO (reduced by LNNA), but insensitive to blockade of guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-α]quinoxalin-1-one (ODQ). In vascular tissues cyclic GMP (cGMP) levels seemed reduced by GYY4137 (not significantly), but were not changed by CORM. These data indicate that CO is able per se to relax isolated ophthalmic artery and to synergize with NO, while H2S counteracts the effect of endogenous NO. CO does not stimulate cGMP production in our system, while H2S may reduce cGMP production stimulated by endogenous NO. These findings provide new insights into the complexities of gas interactions in the control of ophthalmic vascular tone, highlighting potential pharmacological targets for ocular diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. miR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling.

    Directory of Open Access Journals (Sweden)

    Daijiro Hori

    Full Text Available Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening.qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT were followed weekly for pulse wave velocity (PWV and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β induced in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-β in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-β signaling in miR-181a1/b1-/- mice.Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.

  8. Wnt5a Regulates the Assembly of Human Adipose Derived Stromal Vascular Fraction-Derived Microvasculatures.

    Directory of Open Access Journals (Sweden)

    Venkat M Ramakrishnan

    Full Text Available Human adipose-derived stromal vascular fraction (hSVF cells are an easily accessible, heterogeneous cell system that can spontaneously self-assemble into functional microvasculatures in vivo. However, the mechanisms underlying vascular self-assembly and maturation are poorly understood, therefore we utilized an in vitro model to identify potential in vivo regulatory mechanisms. We utilized passage one (P1 hSVF because of the rapid UEA1+ endothelium (EC loss at even P2 culture. We exposed hSVF cells to a battery of angiogenesis inhibitors and found that the pan-Wnt inhibitor IWP2 produced the most significant hSVF-EC networking decrease (~25%. To determine which Wnt isoform(s and receptor(s may be involved, hSVF was screened by PCR for isoforms associated with angiogenesis, with only WNT5A and its receptor, FZD4, being expressed for all time points observed. Immunocytochemistry confirmed Wnt5a protein expression by hSVF. To see if Wnt5a alone could restore IWP2-induced EC network inhibition, recombinant human Wnt5a (0-150 ng/ml was added to IWP2-treated cultures. The addition of rhWnt5a significantly increased EC network area and significantly decreased the ratio of total EC network length to EC network area compared to untreated controls. To determine if Wnt5a mediates in vivo microvascular self-assembly, 3D hSVF constructs containing an IgG isotype control, anti-Wnt5a neutralizing antibody or rhWnt5a were implanted subcutaneously for 2w in immune compromised mice. Compared to IgG controls, anti-Wnt5a treatment significantly reduced vessel length density by ~41%, while rhWnt5a significantly increased vessel length density by ~62%. However, anti-Wnt5a or rhWnt5a did not significantly affect the density of segments and nodes, both of which measure vascular complexity. Taken together, this data demonstrates that endogenous Wnt5a produced by hSVF plays a regulatory role in microvascular self-assembly in vivo. These findings also suggest that

  9. The power of VEGF (vascular endothelial growth factor) family molecules.

    Science.gov (United States)

    Thomas, Jean-Leon; Eichmann, Anne

    2013-05-01

    Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors (VEGFRs) are key regulators of both angiogenesis and neurogenesis. The current issue of CMLS discusses recent literature and work implementing these signals in nervous system development, maintenance and disease pathology.

  10. RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton.

    Science.gov (United States)

    Tang, Lian; Dai, Fan; Liu, Yan; Yu, Xiaoqiang; Huang, Chao; Wang, Yuqin; Yao, Wenjuan

    2018-05-20

    The RhoA/ROCK signaling pathway regulates cell morphology, adhesion, proliferation, and migration. In this study, we investigated the regulatory role of RhoA/ROCK signaling on PDGF-BB-mediated smooth muscle phenotypic modulation and vascular remodeling and clarified the molecular mechanisms behind these effects. PDGF-BB treatment induced the activation of RhoA, ROCK, PDGF-Rβ, and the expression of PDGF-Rβ in HA-VSMCs (human aortic vascular smooth muscle cells). PDGF-Rβ inhibition and RhoA suppression blocked PDGF-BB-induced RhoA activation and ROCK induction. In addition, PDGF-BB-mediated cell proliferation and migration were suppressed by PDGF-Rβ inhibition, RhoA suppression, and ROCK inhibition, suggesting that PDGF-BB promotes phenotypic modulation of HA-VSMCs by activating the RhoA/ROCK pathway via the PDGF receptor. Moreover, suppressing both ROCK1 and ROCK2 blocked cell cycle progression from G0/G1 to S phase by decreasing the transcription and protein expression of cyclin D1, CDK2, and CDK4 via JNK/c-Jun pathway, thus reducing cell proliferation in PDGF-BB-treated HA-VSMCs. ROCK1 deletion, rather than ROCK2 suppression, significantly inhibited PDGF-BB-induced migration by reducing the expression of vimentin and preventing the remodeling of vimentin and phospho-vimentin. Furthermore, ROCK1 deletion suppressed vimentin by inhibiting the phosphorylation of Smad2/3 and the nuclear translocation of Smad4. These findings suggested that ROCK1 and ROCK2 might play different roles in PDGF-BB-mediated cell proliferation and migration in HA-VSMCs. In addition, PDGF-BB and its receptor participated in neointima formation and vascular remodeling by promoting cell cycle protein expression via the JNK pathway and enhancing vimentin expression in a rat balloon injury model; effects that were inhibited by treatment with fasudil. Together, the results of this study reveal a novel mechanism through which RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and

  11. Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Chang Hyun Byon

    2016-10-01

    Full Text Available Oxidative stress represents excessive intracellular levels of reactive oxygen species (ROS, which plays a major role in the pathogenesis of cardiovascular disease. Besides having a critical impact on the development and progression of vascular pathologies including atherosclerosis and diabetic vasculopathy, oxidative stress also regulates physiological signaling processes. As a cell permeable ROS generated by cellular metabolism involved in intracellular signaling, hydrogen peroxide (H2O2 exerts tremendous impact on cardiovascular pathophysiology. Under pathological conditions, increased oxidase activities and/or impaired antioxidant systems results in uncontrolled production of ROS. In a pro-oxidant environment, vascular smooth muscle cells (VSMC undergo phenotypic changes which can lead to the development of vascular dysfunction such as vascular inflammation and calcification. Investigations are ongoing to elucidate the mechanisms for cardiovascular disorders induced by oxidative stress. This review mainly focuses on the role of H2O2 in regulating physiological and pathological signals in VSMC.

  12. Nitric oxide signaling pathway regulates potassium chloride cotransporter-1 mRNA expression in vascular smooth muscle cells.

    Science.gov (United States)

    Di Fulvio, M; Lauf, P K; Adragna, N C

    2001-11-30

    Rat vascular smooth muscle cells (VSMCs) express at least two mRNAs for K-Cl cotransporters (KCC): KCC1 and KCC3. cGMP-dependent protein kinase I regulates KCC3 mRNA expression in these cells. Here, we show evidence implicating the nitric oxide (NO)/cGMP signaling pathway in the expression of KCC1 mRNA, considered to be the major cell volume regulator. VSMCs, expressing soluble guanylyl cyclase (sGC) and PKG-I isoforms showed a time- and concentration-dependent increase in KCC1 mRNA levels after treatment with sodium nitroprusside as demonstrated by semiquantitative RT-PCR. sGC-dependent regulation of KCC1 mRNA expression was confirmed using YC-1, a NO-independent sGC stimulator. The sGC inhibitor LY83583 blocked the effects of sodium nitroprusside and YC-1. Moreover, 8-Br-cGMP increased KCC1 mRNA expression in a concentration- and time-dependent fashion. The 8-Br-cGMP effect was partially blocked by KT5823 but not by actinomycin D. However, actinomycin D and cycloheximide increased basal KCC1 mRNA in an additive manner, suggesting different mechanisms of action for both drugs. These findings suggest that in VSMCs, the NO/cGMP-signaling pathway participates in KCC1 mRNA regulation at the post-transcriptional level.

  13. Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

    Science.gov (United States)

    Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

    2016-04-01

    Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

  14. Laminin promotes vascular network formation in 3D in vitro collagen scaffolds by regulating VEGF uptake.

    Science.gov (United States)

    Stamati, Katerina; Priestley, John V; Mudera, Vivek; Cheema, Umber

    2014-09-10

    Angiogenesis is an essential neovascularisation process, which if recapitulated in 3D in vitro, will provide better understanding of endothelial cell (EC) behaviour. Various cell types and growth factors are involved, with vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 key components. We were able to control the aggregation pattern of ECs in 3D collagen hydrogels, by varying the matrix composition and/or having a source of cells signalling angiogenic proteins. These aggregation patterns reflect the different developmental pathways that ECs take to form different sized tubular structures. Cultures with added laminin and thus increased expression of α6 integrin showed a significant increase (p3D. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Evolutionary aspects of non-cell-autonomous regulation in vascular plants: structural background and models to study

    Directory of Open Access Journals (Sweden)

    Anastasiia I. Evkaikina

    2014-02-01

    Full Text Available Plasmodesmata (PD serve for the exchange of information in form of miRNA, proteins and mRNA between adjacent cells in the course of plant development. This fundamental role of PD is well established in angiosperms but has not yet been traced back to the evolutionary ancient plant taxa where functional studies lag behind studies of PD structure and ontogenetic origin. There is convincing evidence that the ability to form secondary (post-cytokinesis PD, which can connect any adjacent cells, contrary to primary PD which form during cytokinesis and link only cells of the same lineage, appeared in the evolution of higher plants at least twice: in seed plants and in some representatives of the Lycopodiophyta. The (inability to form secondary PD is manifested in the symplastic organization of the shoot apical meristem (SAM which in most taxa of seedless vascular plants differs dramatically from that in seed plants. Lycopodiophyta appear to be suitable models to analyze the transport of developmental regulators via PD in SAMs with symplastic organization both different from, as well as analogous to, that in angiosperms, and to understand the evolutionary aspects of the role of this transport in the morphogenesis of vascular plant taxa.

  16. Roles and regulation of brain glutamate transporters in normal and pathological brain function

    International Nuclear Information System (INIS)

    O'Shea, R.D.

    2001-01-01

    Full text: Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian CNS. Synaptically released Glu acts on both ionotropic (iGluR) and metabotropic receptors, and excessive iGluR activation results in neuronal death (termed excitotoxicity). Removal of Glu from the synapse is thus critical for normal transmission and to prevent excitotoxicity, and is performed exclusively by a family of excitatory amino acid transporters (EAATs, also known as glutamate transporters). Disregulation of Glu transport may contribute to the pathogenesis of many neurodegenerative conditions, and altered expression or function of EAATs has been identified in a number of these pathologies. These studies investigated the functional and pathological effects of EAAT inhibitors in vitro, and developed a novel screening assay for compounds with activity at EAATs. Astrocytic EAATs are responsible for the majority of Glu uptake in brain, so preparations containing both astrocytes and neurones are required to analyse the contribution of EAATs to neuroprotection. Organotypic hippocampal cultures (OHCs), which exhibit many of the features of the intact CNS, were prepared from 11-14 day old Sprague Dawley rats (anaesthetised with halothane). Hippocampal slices (350 μm thick) were maintained on culture well inserts in chemically defined medium. After 2 weeks, cultures were treated with EAAT inhibitors for 3-7 days in the presence or absence of 300 μM Glu. Treatment with most EAAT inhibitors resulted in cell death that was proportional to the Glu concentration in the medium. In contrast, (2S,3S,4R)-2-(carboxycyclopropyl)glycine (L-CCG-III), a competitive substrate at EAATs (and possibly an antagonist at the kainate subtype of iGluR), appeared to be neuroprotective: increased Glu was not toxic in the presence of this drug. These results demonstrate the sensitivity of OHCs to inhibition of Glu uptake, highlighting the importance of EAATs in preventing excitotoxicity. Since modulation of

  17. ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.

    Science.gov (United States)

    Wu, Yanming; Chen, Xiao; Zhou, Qian; He, Qizhi; Kang, Jiuhong; Zheng, Jing; Wang, Kai; Duan, Tao

    2014-01-01

    Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in

  18. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome

    DEFF Research Database (Denmark)

    Liaset, Bjørn; Hao, Qin; Jørgensen, Henry Johs. Høgh

    2011-01-01

    Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by e...... metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.......Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated...... with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1a, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited...

  19. Protein kinase A and C regulate leak potassium currents in freshly isolated vascular myocytes from the aorta.

    Directory of Open Access Journals (Sweden)

    Sébastien Hayoz

    Full Text Available We tested the hypothesis that protein kinase A (PKA inhibits K2P currents activated by protein kinase C (PKC in freshly isolated aortic myocytes. PDBu, the PKC agonist, applied extracellularly, increased the amplitude of the K2P currents in the presence of the "cocktail" of K(+ channel blockers. Gö 6976 significantly reduced the increase of the K2P currents by PDBu suggesting the involvement of either α or β isoenzymes of PKC. We found that forskolin, or membrane permeable cAMP, did not inhibit K2P currents activated by the PKC. However, when PKA agonists were added prior to PDBu, they produced a strong decrease in the K2P current amplitudes activated by PKC. Inhibition of PDBu-elicited K2P currents by cAMP agonists was not prevented by the treatment of vascular smooth muscle cells with PKA antagonists (H-89 and Rp-cAMPs. Zn(2+ and Hg(2+ inhibited K2P currents in one population of cells, produced biphasic responses in another population, and increased the amplitude of the PDBu-elicited K(+ currents in a third population of myocytes, suggesting expression of several K2P channel types. We found that cAMP agonists inhibited biphasic responses and increase of amplitude of the PDBu-elicited K2P currents produced by Zn(2+ and Hg(2. 6-Bnz-cAMp produced a significantly altered pH sensitivity of PDBu-elicited K2P-currents, suggesting the inhibition of alkaline-activated K2P-currents. These results indicate that 6-Bnz-cAMP and other cAMP analogs may inhibit K2P currents through a PKA-independent mechanism. cAMP analogs may interact with unidentified proteins involved in K2P channel regulation. This novel cellular mechanism could provide insights into the interplay between PKC and PKA pathways that regulate vascular tone.

  20. Role of integrin-linked kinase in vascular smooth muscle cells: Regulation by statins and angiotensin II

    International Nuclear Information System (INIS)

    Friedrich, Erik B.; Clever, Yvonne P.; Wassmann, Sven; Werner, Nikos; Boehm, Michael; Nickenig, Georg

    2006-01-01

    Our goal was to characterize the role of integrin-linked kinase (ILK) in vascular smooth muscle cells (VSMC), which play a crucial role in atherogenesis. Transfection of VSMC with wild-type and dominant-negative ILK cDNA constructs revealed that ILK mediates migration and proliferation of VSMC but has no effect on VSMC survival. The pro-atherogenic mediator angiotensin II increases ILK protein expression and kinase activity while statin treatment down-regulates ILK in VSMC. Functionally, ILK is necessary for angiotensin II-mediated VSMC migration and proliferation. In VSMC transduced with dominant-negative ILK, statins mediate an additive inhibition of VSMC migration and proliferation, while transfection with wild-type ILK is sufficient to overcome the inhibitory effects of statin treatment on VSMC migration and proliferation. In vivo, ILK is expressed in VSMC of aortic sections from wild-type mice where it is down-regulated following statin treatment and up-regulated following induction of atherosclerosis in apoE-/- mice. These data identify ILK as a novel target in VSMC for anti-atherosclerotic therapy

  1. Intracellular Na+ regulation of Na+ pump sites in cultured vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Allen, J.C.; Navran, S.S.; Seidel, C.L.; Dennison, D.K.; Amann, J.M.; Jemelka, S.K.

    1989-01-01

    Enzymatically dispersed cells from canine saphenous vein and femoral artery were grown in fetal calf serum and studied at day 0 (freshly dispersed) through confluence in primary culture. Intracellular Na levels (Nai), but not intracellular K (Ki), were increased after 24 h in culture and then decreased to a steady state by 4 days. Na+ pump site number [( 3 H] ouabain binding) increased through day 3 and remained elevated. Nai was still elevated at 2 days when the Na+ pump site number began to increase. Total pump turnover (maximum ouabain-inhibited 86 Rb uptake) reflected the increase in Na+ pump site number. These key events precede the observed increases in both protein production and cellular proliferation. If the same cells are maintained in defined medium, without fetal calf serum, Nai, Ki, and the number of [ 3 H]ouabain binding sites do not change with time. These data are consistent with the suggestion that the initial mitogenic response of vascular smooth muscle cells to fetal calf serum involves an increased Na+ influx, and a Nai accumulation, caused by low Na+ pump density. The synthesis of new pump sites effects a decrease in the accumulated Nai, which may be related to cell proliferation

  2. Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.

    Science.gov (United States)

    Arneson, Douglas; Bhattacharya, Anindya; Shu, Le; Mäkinen, Ville-Petteri; Yang, Xia

    2016-09-09

    Human diseases are commonly the result of multidimensional changes at molecular, cellular, and systemic levels. Recent advances in genomic technologies have enabled an outpour of omics datasets that capture these changes. However, separate analyses of these various data only provide fragmented understanding and do not capture the holistic view of disease mechanisms. To meet the urgent needs for tools that effectively integrate multiple types of omics data to derive biological insights, we have developed Mergeomics, a computational pipeline that integrates multidimensional disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease development. To make the Mergeomics pipeline available to a wider research community, we have implemented an online, user-friendly web server ( http://mergeomics. idre.ucla.edu/ ). The web server features a modular implementation of the Mergeomics pipeline with detailed tutorials. Additionally, it provides curated genomic resources including tissue-specific expression quantitative trait loci, ENCODE functional annotations, biological pathways, and molecular networks, and offers interactive visualization of analytical results. Multiple computational tools including Marker Dependency Filtering (MDF), Marker Set Enrichment Analysis (MSEA), Meta-MSEA, and Weighted Key Driver Analysis (wKDA) can be used separately or in flexible combinations. User-defined summary-level genomic association datasets (e.g., genetic, transcriptomic, epigenomic) related to a particular disease or phenotype can be uploaded and computed real-time to yield biologically interpretable results, which can be viewed online and downloaded for later use. Our Mergeomics web server offers researchers flexible and user-friendly tools to facilitate integration of multidimensional data into holistic views of disease mechanisms in the form of tissue-specific key regulators

  3. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

    International Nuclear Information System (INIS)

    Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun; Song, Sang Heon; Shin, Hwa Kyoung; Bae, Sun Sik

    2015-01-01

    Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs

  4. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Song, Sang Heon [Department of Internal Medicine, Pusan National University Hospital, Busan (Korea, Republic of); Shin, Hwa Kyoung [Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan (Korea, Republic of); Bae, Sun Sik, E-mail: sunsik@pusan.ac.kr [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of)

    2015-08-14

    Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs.

  5. Gender differences in myogenic regulation along the vascular tree of the gerbil cochlea.

    Directory of Open Access Journals (Sweden)

    Katrin Reimann

    Full Text Available Regulation of cochlear blood flow is critical for hearing due to its exquisite sensitivity to ischemia and oxidative stress. Many forms of hearing loss such as sensorineural hearing loss and presbyacusis may involve or be aggravated by blood flow disorders. Animal experiments and clinical outcomes further suggest that there is a gender preference in hearing loss, with males being more susceptible. Autoregulation of cochlear blood flow has been demonstrated in some animal models in vivo, suggesting that similar to the brain, blood vessels supplying the cochlea have the ability to control flow within normal limits, despite variations in systemic blood pressure. Here, we investigated myogenic regulation in the cochlear blood supply of the Mongolian gerbil, a widely used animal model in hearing research. The cochlear blood supply originates at the basilar artery, followed by the anterior inferior cerebellar artery, and inside the inner ear, by the spiral modiolar artery and the radiating arterioles that supply the capillary beds of the spiral ligament and stria vascularis. Arteries from male and female gerbils were isolated and pressurized using a concentric pipette system. Diameter changes in response to increasing luminal pressures were recorded by laser scanning microscopy. Our results show that cochlear vessels from male and female gerbils exhibit myogenic regulation but with important differences. Whereas in male gerbils, both spiral modiolar arteries and radiating arterioles exhibited pressure-dependent tone, in females, only radiating arterioles had this property. Male spiral modiolar arteries responded more to L-NNA than female spiral modiolar arteries, suggesting that NO-dependent mechanisms play a bigger role in the myogenic regulation of male than female gerbil cochlear vessels.

  6. HDAC Inhibition in Vascular Endothelial Cells Regulates the Expression of ncRNAs

    Directory of Open Access Journals (Sweden)

    Haloom Rafehi

    2016-05-01

    Full Text Available While clinical and pre-clinical trials indicate efficacy of histone deacetylase (HDAC inhibitors in disease mediated by dynamic lysine modification, the impact on the expression of non-coding RNAs (ncRNAs remains poorly understood. In this study, we investigate high throughput RNA sequencing data derived from primary human endothelial cells stimulated with HDAC inhibitors suberanilohydroxamic acid (SAHA and Trichostatin A (TSA. We observe robust regulation of ncRNA expression. Integration of gene expression data with histone 3 lysine 9 and 14 acetylation (H3K9/14ac and histone 3 lysine 4 trimethylation (H3K4me3 datasets identified complex and class-specific expression of ncRNAs. We show that EP300 target genes are subject to histone deacetylation at their promoter following HDAC inhibition. This deacetylation drives suppression of protein-coding genes. However, long intergenic non-coding RNAs (lincRNAs regulated by EP300 are activated following HDAC inhibition, despite histone deacetylation. This increased expression was driven by increased H3K4me3 at the gene promoter. For example, elevated promoter H3K4me3 increased lincRNA MALAT1 expression despite broad EP300-associated histone deacetylation. In conclusion, we show that HDAC inhibitors regulate the expression of ncRNA by complex and class-specific epigenetic mechanisms.

  7. Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway.

    Science.gov (United States)

    Guo, Youming; Li, Pengfei; Gao, Lin; Zhang, Jingmei; Yang, Zhirong; Bledsoe, Grant; Chang, Eugene; Chao, Lee; Chao, Julie

    2017-08-01

    Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells (EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin (STZ)-induced diabetic mice, and Caenorhabditis elegans (C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and microRNA-21 (miR-21) and p16 INK 4a synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes. Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 (SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a-SIRT1

  8. Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.

    Science.gov (United States)

    Ahluwalia, A; Jones, M K; Szabo, S; Tarnawski, A S

    2014-04-01

    In some tissues, aging impairs angiogenesis and reduces expression of vascular endothelial growth factor A (VEGF), a fundamental regulator of angiogenesis. We previously examined angiogenesis in aging and young gastric mucosa in vivo and in vitro and showed that an imbalance between expressions of VEGF (pro-angiogenic factor) and endostatin (anti-angiogenic protein) results in an aging-related impairment of angiogenesis in rats. However, the human relevance of these findings, and whether these mechanisms apply to endothelial cells derived from other tissues, is not clear. Since P-STAT3 and P-CREB are transcription factors that, in association with HIF-1α, can activate VEGF gene expression in some cells (e.g., liver cancer cells, vascular smooth muscle cells), we examined the expression of these two proteins in human dermal microvascular endothelial cells (HMVECs) derived from aging and neonatal individuals. We examined and quantified in vitro angiogenesis, expression of VEGF, P-STAT3, P-CREB and importin-α in HMVECs isolated from neonates (neonatal) and a 66 year old subject (aging). We also examined the effects of treatment with exogenous VEGF and endostatin on in vitro angiogenesis in these cells. Endothelial cells isolated from aging individuals had impaired angiogenesis (vs. neonatal endothelial cells) and reduced expression of VEGF mRNA and protein. Aged HMVECs also had reduced importin-α expression, and reduced expression and nuclear translocation of P-STAT3 and P-CREB. Reduced VEGF gene expression in aged HMVECs strongly correlated with the decreased levels of P-STAT3, P-CREB and importin-α in these cells. Our study clearly demonstrates that endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-STAT3 and P-CREB transcription factors in these cells.

  9. KUS121, an ATP regulator, mitigates chorioretinal pathologies in animal models of age-related macular degeneration

    Directory of Open Access Journals (Sweden)

    Yuki Muraoka

    2018-05-01

    Full Text Available Age-related macular degeneration (AMD is a leading cause of blindness among elderly people. The appearance of drusen is a clinical manifestation and a harbinger of both exudative and atrophic AMD. Recently, antibody-based medicines have been used to treat the exudative type. However, they do not restore good vision in patients. Moreover, no effective treatment is available for atrophic AMD. We have created small chemicals (Kyoto University Substances; KUSs that act as ATP regulators inside cells. In the present study, we examined the in vivo efficacy of KUS121 in C-C chemokine receptor type 2-deficient mice, a mouse model of AMD. Systemic administration of KUS121 prevented or reduced drusen-like lesions and endoplasmic reticulum stress, and then substantially mitigated chorioretinal pathologies with significant preservation of visual function. Additionally, we confirmed that long-term oral administration of KUS121 caused no systemic complications in drusen-affected monkeys. ATP regulation by KUSs may represent a novel strategy in the treatment of drusen and prevention of disease progression in AMD.

  10. The urokinase plasminogen activator system components are regulated by vascular endothelial growth factor D in bovine oviduct.

    Science.gov (United States)

    García, Daniela C; Russo-Maenza, Agostina; Miceli, Dora C; Valdecantos, Pablo A; Roldán-Olarte, Mariela

    2018-06-08

    SummaryThe mammalian oviduct plays a pivotal role in the success of early reproductive events. The urokinase plasminogen activator system (uPAS) is present in the bovine oviduct and is involved in extracellular matrix remodelling through plasmin generation. This system can be regulated by several members of the vascular endothelial growth factors (VEGF) and their receptors. In this study, the VEGF-D effect on the regulation of uPAS was evaluated. First, RT-polymerase chain reaction (PCR) analyses were used to evidence the expression of VEGF-D and its receptors in oviductal epithelial cells (BOEC). VEGF-D, VEGFR2 and VEGFR3 transcripts were found in ex vivo and in vitro BOEC, while only VEGFR2 mRNA was present after in vitro conditions. VEGF-D showed a regulatory effect on uPAS gene expression in a dose-dependent manner, inducing an increase in the expression of both uPA and its receptor (uPAR) at 24 h post-induction and decreases in the expression of its inhibitor (PAI-1). In addition, the regulation of cell migration induced by VEGF-D and uPA in BOEC monolayer cultures was analyzed. The wound areas of monolayer cultures incubated with VEGF-D 10 ng/ml or uPA 10 nM were modified and significant differences were found at 24 h for both stimulations. These results indicated that uPAS and VEGF-D systems can modify the arrangement of the bovine oviductal epithelium and contribute to the correct maintenance of the oviductal microenvironment.

  11. Eosinophils are key regulators of perivascular adipose tissue and vascular functionality

    DEFF Research Database (Denmark)

    Withers, Sarah B.; Forman, Ruth; Meza-Perez, Selene

    2017-01-01

    Obesity impairs the relaxant capacity of adipose tissue surrounding the vasculature (PVAT) and has been implicated in resultant obesity-related hypertension and impaired glucose intolerance. Resident immune cells are thought to regulate adipocyte activity. We investigated the role of eosinophils...... in mediating normal PVAT function. Healthy PVAT elicits an anti-contractile effect, which was lost in mice deficient in eosinophils, mimicking the obese phenotype, and was restored upon eosinophil reconstitution. Ex vivo studies demonstrated that the loss of PVAT function was due to reduced bioavailability...... of adiponectin and adipocyte-derived nitric oxide, which was restored after eosinophil reconstitution. Mechanistic studies demonstrated that adiponectin and nitric oxide are released after activation of adipocyte-expressed β3 adrenoceptors by catecholamines, and identified eosinophils as a novel source...

  12. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Bin [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Li, Wei [Department of Gerontology, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Zheng, Qichang [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Qin, Tao [Department of Hepatobiliary Pancreatic Surgery, People' s Hospital of Zhengzhou University, School of Medicine, Zhengzhou University, Zhengzhou 450003 (China); Wang, Kun; Li, Jinjin; Guo, Bing; Yu, Qihong; Wu, Yuzhe; Gao, Yang; Cheng, Xiang; Hu, Shaobo; Kumar, Stanley Naveen [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China); Liu, Sanguang, E-mail: sanguang1998@sina.com [Department of Hepatobiliary Surgery, The Second Hospital, Hebei Medical University, Shijiazhuang 050000 (China); Song, Zifang, E-mail: zsong@hust.edu.cn [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan 430022 (China)

    2015-07-17

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.

  13. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Yang, Bin; Li, Wei; Zheng, Qichang; Qin, Tao; Wang, Kun; Li, Jinjin; Guo, Bing; Yu, Qihong; Wu, Yuzhe; Gao, Yang; Cheng, Xiang; Hu, Shaobo; Kumar, Stanley Naveen; Liu, Sanguang; Song, Zifang

    2015-01-01

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negative effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation

  14. A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia.

    Science.gov (United States)

    Gao, Qinqin; Tang, Jiaqi; Li, Na; Zhou, Xiuwen; Li, Yongmei; Liu, Yanping; Wu, Jue; Yang, Yuxian; Shi, Ruixiu; He, Axin; Li, Xiang; Zhang, Yingying; Chen, Jie; Zhang, Lubo; Sun, Miao; Xu, Zhice

    2017-05-09

    The present study tested the hypothesis that angiotensin II plays a role in the regulation of placental vascular tone, which contributes to hypertension in preeclampsia. Functional and molecular assays were performed in large and micro placental and non-placental vessels from humans and animals. In human placental vessels, angiotensin II induced vasoconstrictions in 78.7% vessels in 155 tests, as referenced to KCl-induced contractions. In contrast, phenylephrine only produced contractions in 3.0% of 133 tests. In non-placental vessels, phenylephrine induced contractions in 76.0% of 67 tests, whereas angiotensin II failed to produce contractions in 75 tests. Similar results were obtained in animal placental and non-placental vessels. Compared with non-placental vessels, angiotensin II receptors and β-adrenoceptors were significantly increased in placental vessels. Compared to the vessels from normal pregnancy, angiotensin II-induced vasoconstrictions were significantly reduced in preeclamptic placentas, which was associated with a decrease in angiotensin II receptors. In addition, angiotensin II and angiotensin converting enzyme in the maternal-placenta circulation in preeclampsia were increased, whereas angiotensin I and angiotensin1-7 concentrations were unchanged. The study demonstrates a selective effect of angiotensin II in maintaining placental vessel tension, which may play an important role in development of hypertension in preeclampsia.

  15. Selective Expression of an Endogenous Inhibitor of FAK Regulates Proliferation and Migration of Vascular Smooth Muscle Cells

    Science.gov (United States)

    Taylor, Joan M.; Mack, Christopher P.; Nolan, Kate; Regan, Christopher P.; Owens, Gary K.; Parsons, J. Thomas

    2001-01-01

    Extracellular matrix signaling via integrin receptors is important for smooth muscle cell (SMC) differentiation during vasculogenesis and for phenotypic modulation of SMCs during atherosclerosis. We previously reported that the noncatalytic carboxyl-terminal protein binding domain of focal adhesion kinase (FAK) is expressed as a separate protein termed FAK-related nonkinase (FRNK) and that ectopic expression of FRNK can attenuate FAK activity and integrin-dependent signaling (A. Richardson and J. T. Parsons, Nature 380:538–540, 1996). Herein we report that in contrast to FAK, which is expressed ubiquitously, FRNK is expressed selectively in SMCs, with particularly high levels observed in conduit blood vessels. FRNK expression was low during embryonic development, was significantly upregulated in the postnatal period, and returned to low but detectable levels in adult tissues. FRNK expression was also dramatically upregulated following balloon-induced carotid artery injury. In cultured rat aortic smooth muscle cells, overexpression of FRNK attenuated platelet-derived growth factor (PDGF)-BB-induced migration and also dramatically inhibited [3H]thymidine incorporation upon stimulation with PDGF-BB or 10% serum. These effects were concomitant with a reduction in SMC proliferation. Taken together, these data indicate that FRNK acts as an endogenous inhibitor of FAK signaling in SMCs. Furthermore, increased FRNK expression following vascular injury or during development may alter the SMC phenotype by negatively regulating proliferative and migratory signals. PMID:11238893

  16. Regulation of capacitative and non-capacitative Ca2+ entry in A7r5 vascular smooth muscle cells

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    COLIN W TAYLOR

    2004-01-01

    Full Text Available A capacitative Ca2+ entry (CCE pathway, activated by depletion of intracellular Ca2+ stores, is thought to mediate much of the Ca2+ entry evoked by receptors that stimulate phospholipase C (PLC. However, in A7r5 vascular smooth muscle cells, vasopressin, which stimulates PLC, empties intracellular Ca2+ stores but simultaneously inhibits their ability to activate CCE. The diacylglycerol produced with the IP3 that empties the stores is metabolized to arachidonic and this leads to activation of nitric oxide (NO synthase, production of NO and cyclic GMP, and consequent activation of protein kinase G. The latter inhibits CCE. In parallel, NO directly activates a non-capacitative Ca2+ entry (NCCE pathway, which is entirely responsible for the Ca2+ entry that occurs in the presence of vasopressin. This reciprocal regulation of two Ca2+ entry pathways ensures that there is sequential activation of first NCCE in the presence of vasopressin, and then a transient activation of CCE when vasopressin is removed. We suggest that the two routes for Ca2+ entry may selectively direct Ca2+ to processes that mediate activation and then recovery of the cell.

  17. Up-regulation of intestinal vascular endothelial growth factor by Afa/Dr diffusely adhering Escherichia coli.

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    Gaëlle Cane

    Full Text Available BACKGROUND: Angiogenesis has been recently described as a novel component of inflammatory bowel disease pathogenesis. The level of vascular endothelial growth factor (VEGF has been found increased in Crohn's disease and ulcerative colitis mucosa. To question whether a pro-inflammatory Escherichia coli could regulate the expression of VEGF in human intestinal epithelial cells, we examine the response of cultured human colonic T84 cells to infection by E. coli strain C1845 that belongs to the typical Afa/Dr diffusely adhering E. coli family (Afa/Dr DAEC. METHODOLOGY: VEGF mRNA expression was examined by Northern blotting and q-PCR. VEGF protein levels were assayed by ELISA and its bioactivity was analysed in endothelial cells. The bacterial factor involved in VEGF induction was identified using recombinant E. coli expressing Dr adhesin, purified Dr adhesin and lipopolysaccharide. The signaling pathway activated for the up-regulation of VEGF was identified using a blocking monoclonal anti-DAF antibody, Western blot analysis and specific pharmacological inhibitors. PRINCIPAL FINDINGS: C1845 bacteria induce the production of VEGF protein which is bioactive. VEGF is induced by adhering C1845 in both a time- and bacteria concentration-dependent manner. This phenomenon is not cell line dependent since we reproduced this observation in intestinal LS174, Caco2/TC7 and INT407 cells. Up-regulation of VEGF production requires: (1 the interaction of the bacterial F1845 adhesin with the brush border-associated decay accelerating factor (DAF, CD55 acting as a bacterial receptor, and (2 the activation of a Src protein kinase upstream of the activation of the Erk and Akt signaling pathways. CONCLUSIONS: Results demonstrate that a Afa/Dr DAEC strain induces an adhesin-dependent activation of DAF signaling that leads to the up-regulation of bioactive VEGF in cultured human intestinal cells. Thus, these results suggest a link between an entero-adherent, pro

  18. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.

    Science.gov (United States)

    Chen, Jun; Joshi, Shailen K; DiDomenico, Stanley; Perner, Richard J; Mikusa, Joe P; Gauvin, Donna M; Segreti, Jason A; Han, Ping; Zhang, Xu-Feng; Niforatos, Wende; Bianchi, Bruce R; Baker, Scott J; Zhong, Chengmin; Simler, Gricelda H; McDonald, Heath A; Schmidt, Robert G; McGaraughty, Steve P; Chu, Katharine L; Faltynek, Connie R; Kort, Michael E; Reilly, Regina M; Kym, Philip R

    2011-05-01

    Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Notch signaling regulates platelet-derived growth factor receptor-β expression in vascular smooth muscle cells

    NARCIS (Netherlands)

    Jin, S.; Hansson, E.M.; Tikka, S.; Lanner, F.; Sahlgren, C.; Farnebo, F.; Baumann, M.; Kalimo, H.; Lendahl, U.

    2008-01-01

    Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor

  20. The perspective of the vascular surgery trainee on new ACGME regulations, fatigue, resident training, and patient safety.

    Science.gov (United States)

    De Martino, Randall R; Brewster, L P; Kokkosis, A A; Glass, C; Boros, M; Kreishman, P; Kauvar, D A; Farber, A

    2011-11-01

    To assess the opinions of vascular surgery trainees on the new Accreditation Council for Graduate Medical Education (ACGME) guidelines. A questionnaire was developed and electronically distributed to trainee members of the Society for Vascular Surgery. Of 238 eligible vascular trainees, 38 (16%) participated. Respondents were predominantly 30 to 35 years of age (47%), male (69%), in 2-year fellowship (73%), and at large academic centers (61%). Trainees report occasionally working while fatigued (63%). Fellows were more likely to report for duty while fatigued (P = .012) than integrated vascular residents. Respondents thought further work-hour restrictions would not improve patient care or training (P life. Respondents reported that duty hours should vary by specialty (81%) and allow flexibility in the last years of training (P balanced against the need to adequately train vascular surgeons.

  1. Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

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    Simona-Adriana Manea

    2018-06-01

    Full Text Available Reactive oxygen species (ROS generated by up-regulated NADPH oxidase (Nox contribute to structural-functional alterations of the vascular wall in diabetes. Epigenetic mechanisms, such as histone acetylation, emerged as important regulators of gene expression in cardiovascular disorders. Since their role in diabetes is still elusive we hypothesized that histone deacetylase (HDAC-dependent mechanisms could mediate vascular Nox overexpression in diabetic conditions. Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive vehicle or suberoylanilide hydroxamic acid (SAHA, a pan-HDAC inhibitor. In vitro studies were performed on a human aortic smooth muscle cell (SMC line. Aortic SMCs typically express Nox1, Nox4, and Nox5 subtypes. HDAC1 and HDAC2 proteins along with Nox1, Nox2, and Nox4 levels were found significantly elevated in the aortas of diabetic mice compared to non-diabetic animals. Treatment of diabetic mice with SAHA mitigated the aortic expression of Nox1, Nox2, and Nox4 subtypes and NADPH-stimulated ROS production. High concentrations of glucose increased HDAC1 and HDAC2 protein levels in cultured SMCs. SAHA significantly reduced the high glucose-induced Nox1/4/5 expression, ROS production, and the formation malondialdehyde-protein adducts in SMCs. Overexpression of HDAC2 up-regulated the Nox1/4/5 gene promoter activities in SMCs. Physical interactions of HDAC1/2 and p300 proteins with Nox1/4/5 promoters were detected at the sites of active transcription. High glucose induced histone H3K27 acetylation enrichment at the promoters of Nox1/4/5 genes in SMCs. The novel data of this study indicate that HDACs mediate vascular Nox up-regulation in diabetes. HDAC inhibition reduces vascular ROS production in experimental diabetes, possibly by a mechanism involving negative regulation of Nox expression. Keywords: NADPH oxidase, Epigenetics, HDAC, Histone acetylation, Diabetes

  2. Vascular endothelial growth factor C promotes cervical cancer cell invasiveness via regulation of microRNA-326/cortactin expression.

    Science.gov (United States)

    Cheng, Yang; Jiang, Shuyi; Yuan, Jin; Liu, Junxiu; Simoncini, Tommaso

    2018-04-16

    Vascular endothelial growth factor C (VEGF-C) accelerates cervical cancer metastasis, while the detailed mechanism remains largely unknown. Recent evidence indicates that microRNA play a crucial role in controlling cancer cell invasiveness. In the present study, we investigated the role of miR-326 in VEGF-C-induced cervical cancer cell invasion. VEGF-C expression was higher and miR-326 was much lower in primary cervical cancer specimens than that in non-cancerous specimens, and a negative correlation between VEGF-C and miR-326 was found. On cervical carcinoma cell line SiHa cells, treatment with VEGF-C downregulated miR-326 level and increased cortactin protein expression. Transfection with miR-326 mimic reversed cortactin expression induced by VEGF-C, suggesting that VEGF-C increased cortactin via downregulation of miR-326. VEGF-C activated c-Src and c-Src inhibitor PP2 abolished VEGF-C effect on miR-326 and cortactin expression, implying that VEGF-C regulated miR-326/cortactin via c-Src signaling. VEGF-C promoted SiHa cell invasion index, which was largely inhibited by transfection with miR-326 antagonist or by siRNA against cortactin. In conclusion, our findings implied that VEGF-C reduced miR-326 expression and increased cortactin expression through c-Src signaling, leading to enhanced cervical cancer invasiveness. This may shed light on potential therapeutic strategies for cervical cancer therapy.

  3. It's All about Timing: The Involvement of Kir4.1 Channel Regulation in Acute Ischemic Stroke Pathology

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    Meagan Milton

    2018-02-01

    Full Text Available An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009. For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+ and chloride channels (Vella et al., 2015. This astroglial swelling may be overwhelmed, under ischemic conditions, due to the increased levels of glutamate and extracellular K+ (Lai et al., 2014; Vella et al., 2015. The increase in extracellular K+ contributes to neuronal damage and loss through the initiation of harmful secondary cascades (Nwaobi et al., 2016. Reducing the amount of extracellular K+ could, in theory, limit or prevent neuronal damage and loss resulting in an improved prognosis for individuals following ischemic stroke. Kir4.1, an inwardly rectifying K+ channel, has demonstrated an ability to regulate the rapid reuptake of this ion to return the cell to basal levels allowing it to fire again in rapid transmission (Sibille et al., 2015. Despite growing interest in this area, the underlying mechanism suggesting that neuroprotection could occur through modification of the Kir4.1 channel's activity has yet to be described. The purpose of this review is to examine the current literature and propose potential underlying mechanisms involving Kir4.1, specially the mammalian target of rapamycin (mTOR and/or autophagic pathways, in the pathogenesis of ischemic stroke. The hope is that this review will instigate further investigation of Kir4.1 as a modulator of stroke pathology.

  4. The targeting expression of the vascular endothelial growth factor gene in endothelial cells regulated by HRE.ppET-1.

    Science.gov (United States)

    Zheng, Xiangrong; Zhang, Shangshang; Yang, Yujia; Wang, Xia; Zhong, Le; Yu, Xiaohe

    2008-11-01

    The success of gene therapy depends largely on the efficacy of gene delivery vector systems that can deliver genes to target organs or cells selectively and efficiently with minimal toxicity. Here, we show that by using the HRE.ppET-1 regulatory element, we were able to restrict expression of the transgene of vascular endothelial growth factor (VEGF) to endothelial cells exclusively in hypoxic conditions. Eukaryotic expression vectors such as pEGFP-HRE.ppET-1, pcDNA3.1-VEGF+Pa, pcDNA3.1-ppET-1+ EGF+Pa, and pcDNA3.1-HRE.ppET-1+VEGF+Pa were constructed by using a series of nuclear molecule handling methods like PCR, enzyme digestion. The recombinant vectors were transfected into HUVEC cells and HL7702 cells by the lipofectin method. GFP expression was observed with a fluorescence microscope to validate the specificity of expression in endothelial cells under the regulation of HRE.ppET-1 element. Cobalt chloride (final concentration 100 mumol/L) was added to the medium to mimic hypoxia in vitro. After transfection of vectors, the expression of VEGF mRNA was detected by RT-PCR, and the expression of VEGF was detected by Western blotting and ELISA methods under normoxia and hypoxia, respectively. The cell proliferation rate was detected by the MTT test. The expression of GFP revealed that the exterior gene was transcripted effectively in endothelial cells regulated by the HRE.ppET-1 element, while the expression of GFP was very weak in nonendothelial cells. The results of RT-PCR, Western blotting and ELISA showed that VEGF gene expression in the pcDNA3.1-HRE.ppET-1+VEGF+Pa group and in the pcDNA3.1-ppET-1+VEGF+Pa group was higher in hypoxia than it was in normoxia (PHRE.ppET-1 element was expressed specifically in endothelial cells, and can increase the expression of VEGF in hypoxia and stimulate proliferation of endothelial cells. Taking advantage of these facts could greatly improve the efficiency of gene therapy. The vector would be valuable for various gene transfer

  5. Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition

    NARCIS (Netherlands)

    C.J. Slager (Cornelis); J. Kloet (Jeroen); J.A.F. Oomen; J.C.H. Schuurbiers (Johan); B.J. de Smet; M.J. Post (Mark); D.P.V. de Kleijn (Dominique); G. Pasterkamp (Gerard); R. Krams (Rob); C. Borst (Cornelius); J.J. Wentzel (Jolanda); I. Andhyiswara (Ivan)

    2001-01-01

    textabstractBACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA

  6. Initiation and Propagation of Vascular Calcification Is Regulated by a Concert of Platelet- and Smooth Muscle Cell-Derived Extracellular Vesicles

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    Leon J. Schurgers

    2018-04-01

    Full Text Available The ageing population continues to suffer from its primary killer, cardiovascular disease (CVD. Despite recent advances in interventional medicinal and surgical therapies towards the end of the 20th century, the epidemic of cardiovascular disease has not been halted. Yet, rather than receding globally, the burden of CVD has risen to become a top cause of morbidity and mortality worldwide. Most CVD arises from thrombotic rupture of an atherosclerotic plaque, the pathologic thickening of coronary and carotid artery segments and subsequent distal ischemia in heart or brain. In fact, one-fifth of deaths are directly attributable to thrombotic rupture of a vulnerable plaque. Atherosclerotic lesion formation is caused by a concert of interactions between circulating leukocytes and platelets, interacting with the endothelial barrier, signalling into the arterial wall by the release of cytokines and extracellular vesicles (EVs. Both platelet- and cell-derived EVs represent a novel mechanism of cellular communication, particularly by the transport and transfer of cargo and by reprogramming of the recipient cell. These interactions result in phenotypic switching of vascular smooth muscle cells (VSMCs causing migration and proliferation, and subsequent secretion of EVs. Loss of VSMCs attracts perivascular Mesenchymal Stem Cells (MSCs from the adventitia, which are a source of VSMCs and contribute to repair after vascular injury. However, continuous stress stimuli eventually switch phenotype of cells into osteochondrogenic VSMCs facilitating vascular calcification. Although Virchow’s triad is over 100 years old, it is a reality that is accurate today. It can be briefly summarised as changes in the composition of blood (platelet EVs, alterations in the vessel wall (VSMC phenotypic switching, MSC infiltration and EV release and disruption of blood flow (atherothrombosis. In this paper, we review the latest relevant advances in the identification of

  7. Calcium dynamics in vascular smooth muscle

    OpenAIRE

    Amberg, Gregory C.; Navedo, Manuel F.

    2013-01-01

    Smooth muscle cells are ultimately responsible for determining vascular luminal diameter and blood flow. Dynamic changes in intracellular calcium are a critical mechanism regulating vascular smooth muscle contractility. Processes influencing intracellular calcium are therefore important regulators of vascular function with physiological and pathophysiological consequences. In this review we discuss the major dynamic calcium signals identified and characterized in vascular smooth muscle cells....

  8. Amphetamine and environmentally induced hyperthermia differentially alter the expression of genes regulating vascular tone and angiogenesis in the meninges and associated vasculature.

    Science.gov (United States)

    Thomas, Monzy; George, Nysia I; Patterson, Tucker A; Bowyer, John F

    2009-10-01

    An amphetamine (AMPH) regimen that does not produce a prominent blood-brain barrier breakdown was shown to significantly alter the expression of genes regulating vascular tone, immune function, and angiogenesis in vasculature associated with arachnoid and pia membranes of the forebrain. Adult-male Sprague-Dawley rats were given either saline injections during environmentally-induced hyperthermia (EIH) or four doses of AMPH with 2 h between each dose (5, 7.5, 10, and 10 mg/kg d-AMPH, s.c.) that produced hyperthermia. Rats were sacrificed either 3 h or 1 day after dosing, and total RNA and protein was isolated from the meninges, arachnoid and pia membranes, and associated vasculature (MAV) that surround the forebrain. Vip, eNos, Drd1a, and Edn1 (genes regulating vascular tone) were increased by either EIH or AMPH to varying degrees in MAV, indicating that EIH and AMPH produce differential responses to enhance vasodilatation. AMPH, and EIH to a lesser extent, elicited a significant inflammatory response at 3 h as indicated by an increased MAV expression of cytokines Il1b, Il6, Ccl-2, Cxcl1, and Cxcl2. Also, genes related to heat shock/stress and disruption of vascular homeostasis such as Icam1 and Hsp72 were also observed. The increased expression of Ctgf and Timp1 and the decreased expression of Akt1, Anpep, and Mmp2 and Tek (genes involved in stimulating angiogenesis) from AMPH exposure suggest that angiogenesis was arrested or disrupted in MAV to a greater extent by AMPH compared to EIH. Alterations in vascular-related gene expression in the parietal cortex and striatum after AMPH were less in magnitude than in MAV, indicating less of a disruption of vascular homeostasis in these two regions. Changes in the levels of insulin-like growth factor binding proteins Igfbp1, 2, and 5 in MAV, compared to those in striatum and parietal cortex, imply an interaction between these regions to regulate the levels of insulin-like growth factor after AMPH damage. Thus, the

  9. Arabidopsis VASCULAR-RELATED UNKNOWN PROTEIN1 Regulates Xylem Development and Growth by a Conserved Mechanism That Modulates Hormone Signaling1[W][OPEN

    Science.gov (United States)

    Grienenberger, Etienne; Douglas, Carl J.

    2014-01-01

    Despite a strict conservation of the vascular tissues in vascular plants (tracheophytes), our understanding of the genetic basis underlying the differentiation of secondary cell wall-containing cells in the xylem of tracheophytes is still far from complete. Using coexpression analysis and phylogenetic conservation across sequenced tracheophyte genomes, we identified a number of Arabidopsis (Arabidopsis thaliana) genes of unknown function whose expression is correlated with secondary cell wall deposition. Among these, the Arabidopsis VASCULAR-RELATED UNKNOWN PROTEIN1 (VUP1) gene encodes a predicted protein of 24 kD with no annotated functional domains but containing domains that are highly conserved in tracheophytes. Here, we show that the VUP1 expression pattern, determined by promoter-β-glucuronidase reporter gene expression, is associated with vascular tissues, while vup1 loss-of-function mutants exhibit collapsed morphology of xylem vessel cells. Constitutive overexpression of VUP1 caused dramatic and pleiotropic developmental defects, including severe dwarfism, dark green leaves, reduced apical dominance, and altered photomorphogenesis, resembling brassinosteroid-deficient mutants. Constitutive overexpression of VUP homologs from multiple tracheophyte species induced similar defects. Whole-genome transcriptome analysis revealed that overexpression of VUP1 represses the expression of many brassinosteroid- and auxin-responsive genes. Additionally, deletion constructs and site-directed mutagenesis were used to identify critical domains and amino acids required for VUP1 function. Altogether, our data suggest a conserved role for VUP1 in regulating secondary wall formation during vascular development by tissue- or cell-specific modulation of hormone signaling pathways. PMID:24567189

  10. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development.

    Science.gov (United States)

    Hilton, Matthew J; Tu, Xiaolin; Cook, Julie; Hu, Hongliang; Long, Fanxin

    2005-10-01

    Indian hedgehog (Ihh) controls multiple aspects of endochondral skeletal development, including proliferation and maturation of chondrocytes, osteoblast development and cartilage vascularization. Although it is known that Gli transcription factors are key effectors of hedgehog signaling, it has not been established which Gli protein mediates Ihh activity in skeletal development. Here, we show that removal of Gli3 in Ihh-null mouse embryos restored normal proliferation and maturation of chondrocytes, but only partially rescued the defects in osteoblast development and cartilage vascularization. Remarkably, in both Ihh-/- and Ihh-/-; Gli3-/- embryos, vascularization promoted osteoblast development in perichondrial progenitor cells. Our results not only establish Gli3 as a critical effector for Ihh activity in the developing skeleton, but also identify an osteogenic role for a vasculature-derived signal, which integrates with Ihh and Wnt signals to determine the osteoblast versus chondrocyte fate in the mesenchymal progenitors.

  11. Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling.

    Science.gov (United States)

    Cao, Wei; Chang, Tuanjie; Li, Xiao-Qiang; Wang, Rui; Wu, Lingyun

    2017-02-01

    Increased production of methylglyoxal (MG) in vascular tissues is one of the causative factors for vascular remodelling in different subtypes of metabolic syndrome, including hypertension and insulin resistance. Fructose-induced up-regulation of aldolase B (AldoB) contributes to increased vascular MG production but the underlying mechanisms are unclear. Serum levels of MG and fructose were determined in diabetic patients with hypertension. MG level had significant positive correlations with blood pressure and fructose level respectively. C57BL/6 mice were fed with control or fructose-enriched diet for 3 months and ultrasonographic and histologic analyses were performed to evaluate arterial structural changes. Fructose-fed mice exhibited hypertension and high levels of serum MG with normal glucose level. Fructose intake increased blood vessel wall thickness and vascular smooth muscle cell (VSMC) proliferation. Western blotting and real-time PCR analysis revealed that AldoB level was significantly increased in both the aorta of fructose-fed mice and the fructose-treated VSMCs, whereas aldolase A (AldoA) expression was not changed. The knockdown of AldoB expression prevented fructose-induced MG overproduction and VSMC proliferation. Moreover, fructose significantly increased carbohydrate-responsive element-binding protein (ChREBP), phosphorylated FoxO1/3α and Akt1 levels. Fructose induced translocation of ChREBP from the cytosol to nucleus and activated AldoB gene expression, which was inhibited by the knockdown of ChREBP. Meanwhile, fructose caused FoxO1/3α shuttling from the nucleus to cytosol and inhibited its binding to AldoB promoter region. Fructose-induced AldoB up-regulation was suppressed by Akt1 inhibitor but enhanced by FoxO1/3α siRNA. Collectively, fructose activates ChREBP and inactivates FoxO1/3α pathways to up-regulate AldoB expression and MG production, leading to vascular remodelling. © 2017 The Author(s). published by Portland Press Limited on

  12. Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia.

    Science.gov (United States)

    Zhang, Yanan; Zhang, Chunlian; Li, Haiou; Hou, Jingdong

    2017-10-14

    Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is associated with endothelial dysfunction. The prevalence of OSA is linked to an epidemic of obesity. CIH has recently been reported to cause endothelial dysfunction in diet-induced obese animals by exaggerating oxidative stress and inflammation, but the underlying mechanism remains unclear. PPAR-γ, a ligand-inducible transcription factor that exerts anti-oxidant and anti-inflammatory effects, is down-regulated in the peripheral tissues in diet-induce obesity. We tested the hypothesis that down-regulation of vascular PPAR-γ in diet-induced obesity enhances inflammation and oxidative stress in response to CIH, resulting in endothelial dysfunction. Male C57BL/6 mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) and simultaneously exposed to CIH or intermittent air for 6 weeks. An additional HFD group received a combination of CIH and PPAR-γ agonist pioglitazone for 6 weeks. Endothelial-dependent vasodilation was impaired only in HFD group exposed to CIH, compared with other groups, but was restored by concomitant pioglitazone treatment. Molecular studies revealed that vascular PPAR-γ expression and activity were reduced in HFD groups, compared with LFD groups, but were reversed by pioglitazone treatment. In addition, CIH elevated vascular expression of NADPH oxidase 4 and dihydroethidium fluorescence, and increased expression of proinflammatory cytokines TNF-α and IL-1β in both LFD and HFD groups, but these increases was significantly greater in HFD group, along with decreased vascular eNOS activity. Pioglitazone treatment of HFD group prevented CIH-induced changes in above molecular markers. The results suggest that HFD-induced obesity down-regulates vascular PPAR-γ, which results in exaggerated oxidative stress and inflammation in response to CIH, contributing to endothelial dysfunction. This finding may provide new insights into the mechanisms by which OSA

  13. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

    NARCIS (Netherlands)

    Gupta, Rajat M.; Hadaya, Joseph; Trehan, Aditi; Zekavat, Seyedeh M.; Roselli, Carolina; Klarin, Derek; Emdin, Connor A.; Hilvering, Catharina R.E.; Bianchi, Valerio; Mueller, Christian; Khera, Amit V.; Ryan, Russell J.H.; Engreitz, Jesse M.; Issner, Robbyn; Shoresh, Noam; Epstein, Charles B.; de Laat, Wouter; Brown, Jonathan D.; Schnabel, Renate B.; Bernstein, Bradley E.; Kathiresan, Sekar

    2017-01-01

    Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common

  14. Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology

    NARCIS (Netherlands)

    Berner, A. K.; Brouwers, O.; Pringle, R.; Klaassen, I.; Colhoun, L.; McVicar, C.; Brockbank, S.; Curry, J. W.; Miyata, T.; Brownlee, M.; Schlingemann, R. O.; Schalkwijk, C.; Stitt, A. W.

    2012-01-01

    Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology.

  15. Transcytosis Involvement in Transport System and Endothelial Permeability of Vascular Leakage during Dengue Virus Infection

    Directory of Open Access Journals (Sweden)

    Chanettee Chanthick

    2018-02-01

    Full Text Available The major role of endothelial cells is to maintain homeostasis of vascular permeability and to preserve the integrity of vascular vessels to prevent fluid leakage. Properly functioning endothelial cells promote physiological balance and stability for blood circulation and fluid components. A monolayer of endothelial cells has the ability to regulate paracellular and transcellular pathways for transport proteins, solutes, and fluid. In addition to the paracellular pathway, the transcellular pathway is another route of endothelial permeability that mediates vascular permeability under physiologic conditions. The transcellular pathway was found to be associated with an assortment of disease pathogeneses. The clinical manifestation of severe dengue infection in humans is vascular leakage and hemorrhagic diatheses. This review explores and describes the transcellular pathway, which is an alternate route of vascular permeability during dengue infection that corresponds with the pathologic finding of intact tight junction. This pathway may be the route of albumin transport that causes endothelial dysfunction during dengue virus infection.

  16. Electron histochemical and autoradiographic studies of vascular smooth muscle cell

    International Nuclear Information System (INIS)

    Kameyama, Kohji; Aida, Takeo; Asano, Goro

    1982-01-01

    The authors have studied the vascular smooth muscle cell in the aorta and the arteries of brain, heart in autopsied cases, cholesterol fed rabbits and canine through electron histochemical and autoradiographic methods, using 3 H-proline and 3 H-thymidine. The vascular changes are variable presumably due to the functional and morphological difference of vessels. Aging, pathological condition and physiological requirement induce the disturbances of vascular functions as contractility. According to various pathological conditions, the smooth muscle cell altered their shape, surface properties and arrangement of subcellular organelles including changes in number. The morphological features of arteries during aging is characterized by the thickening of endothelium and media. Decreasing cellularity and increasing collagen contents in media. The autoradiographic and histochemical observations using periodic acid methenamine silver (PAM) and ruthenium red stains demonstrated that the smooth muscle cell is a connective tissue synthetic cell. The PAM impregnation have proved that the small bundle of microfilaments become associated with small conglomerate of collagen and elastic fibers. Cytochemical examination will provide sufficient evidence to establish the contribution of subcellular structure. The acid phosphatase play an important role in vascular disease and they are directly involved in cellular lipid metabolism in cholesterol fed animals, and the activity of Na-K ATPase on the plasma membrane may contribute to the regulation of vascular blood flow and vasospasms. Direct injury and subsequent abnormal contraction of smooth muscle cell may initiate increased permeability of plasma protein and lipid in the media layer and eventually may developed and enhance arteriosclerosis. (author)

  17. Otosclerosis: Temporal Bone Pathology.

    Science.gov (United States)

    Quesnel, Alicia M; Ishai, Reuven; McKenna, Michael J

    2018-04-01

    Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling.

    Science.gov (United States)

    Devallière, Julie; Charreau, Béatrice

    2011-11-15

    A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation

    International Nuclear Information System (INIS)

    Li, Shang; Dang, Yuan Ye; Oi Lam Che, Ginny; Kwan, Yiu Wa; Chan, Shun Wan; Leung, George Pak Heng; Lee, Simon Ming Yuen; Hoi, Maggie Pui Man

    2014-01-01

    In ischemic disorders such as chronic wounds and myocardial ischemia, there is inadequate tissue perfusion due to vascular insufficiency. Besides, it has been observed that prolonged use of anti-angiogenic agents in cancer therapy produces cardiovascular toxicity caused by impaired vessel integrity and regeneration. In the present study, we used VEGFR tyrosine kinase inhibitor II (VRI) to chemically induce vascular insufficiency in zebrafish in vivo and human umbilical vein endothelial cells (HUVEC) in vitro to further study the mechanisms of vascular morphogenesis in these pathological conditions. We also explored the possibility of treating vascular insufficiency by enhancing vascular regeneration and repair with pharmacological intervention. We observed that pretreatment of VRI induced blood vessel loss in developing zebrafish by inhibiting angiogenesis and increasing endothelial cell apoptosis, accompanied by down-regulation of kdr, kdrl and flt-1 genes expression. The VRI-induced blood vessel loss in zebrafish could be restored by post-treatment of calycosin, a cardiovascular protective isoflavone. Similarly, VRI induced cytotoxicity and apoptosis in HUVEC which could be rescued by calycosin post-treatment. Further investigation of the underlying mechanisms showed that the PI3K/AKT/Bad cell survival pathway was a main contributor of the vascular regenerative effect of calycosin. These findings indicated that the cardiovascular toxicity in anti-angiogenic therapy was mainly caused by insufficient endothelial cell survival, suggesting its essential role in vascular integrity, repair and regeneration. In addition, we showed that VRI-induced blood vessel loss in zebrafish represented a simple and effective in vivo model for studying vascular insufficiency and evaluating cancer drug vascular toxicities. - Highlights: • In vivo VRI model • Rescue effects of calycosin • Calycosin EC survival pathways

  20. Possible role of mechanical force in regulating regeneration of the vascularized fat flap inside a tissue engineering chamber.

    Science.gov (United States)

    Ye, Yuan; Yuan, Yi; Lu, Feng; Gao, Jianhua

    2015-12-01

    In plastic and reconstructive surgery, adipose tissue is widely used as effective filler for tissue defects. Strategies for treating soft tissue deficiency, which include free adipose tissue grafts, use of hyaluronic acid, collagen injections, and implantation of synthetic materials, have several clinical limitations. With the aim of overcoming these limitations, researchers have recently utilized tissue engineering chambers to produce large volumes of engineered vascularized fat tissue. However, the process of growing fat tissue in a chamber is still relatively limited, and can result in unpredictable or dissatisfactory final tissue volumes. Therefore, detailed understanding of the process is both necessary and urgent. Many studies have shown that mechanical force can change the function of cells via mechanotransduction. Here, we hypothesized that, besides the inflammatory response, one of the key factors to control the regeneration of vascularized fat flap inside a tissue engineering chamber might be the balance of mechanical forces. To test our hypothesis, we intend to change the balance of forces by means of measures in order to make the equilibrium point in favor of the direction of regeneration. If those measures proved to be feasible, they could be applied in clinical practice to engineer vascularized adipose tissue of predictable size and shape, which would in turn help in the advancement of tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Computational Pathology

    Science.gov (United States)

    Louis, David N.; Feldman, Michael; Carter, Alexis B.; Dighe, Anand S.; Pfeifer, John D.; Bry, Lynn; Almeida, Jonas S.; Saltz, Joel; Braun, Jonathan; Tomaszewski, John E.; Gilbertson, John R.; Sinard, John H.; Gerber, Georg K.; Galli, Stephen J.; Golden, Jeffrey A.; Becich, Michael J.

    2016-01-01

    Context We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective To define the scope and needs of computational pathology. Data Sources A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and non-pathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID:26098131

  2. Molecular Regulation of the Mitochondrial F1Fo-ATPsynthase: Physiological and Pathological Significance of the Inhibitory Factor 1 (IF 1

    Directory of Open Access Journals (Sweden)

    Danilo Faccenda

    2012-01-01

    Full Text Available In mammals, the mitochondrial F1Fo-ATPsynthase sets out the energy homeostasis by producing the bulk of cellular ATP. As for every enzyme, the laws of thermodynamics command it; however, it is privileged to have a dedicated molecular regulator that controls its rotation. This is the so-called ATPase Inhibitory Factor 1 (IF1 that blocks its reversal to avoid the consumption of cellular ATP when the enzyme acts as an ATP hydrolase. Recent evidence has also demonstrated that IF1 may control the alignment of the enzyme along the mitochondrial inner membrane, thus increasing the interest for the molecule. We conceived this review to outline the fundamental knowledge of the F1Fo-ATPsynthase and link it to the molecular mechanisms by which IF1 regulates its way of function, with the ultimate goal to highlight this as an important and possibly unique means to control this indispensable enzyme in both physiological and pathological settings.

  3. Differential regulation of amyloid precursor protein sorting with pathological mutations results in a distinct effect on amyloid-β production.

    Science.gov (United States)

    Lin, Yen-Chen; Wang, Jia-Yi; Wang, Kai-Chen; Liao, Jhih-Ying; Cheng, Irene H

    2014-11-01

    The deposition of amyloid-β (Aβ) peptide, which is generated from amyloid precursor protein (APP), is the pathological hallmark of Alzheimer's disease (AD). Three APP familial AD mutations (D678H, D678N, and H677R) located at the sixth and seventh amino acid of Aβ have distinct effect on Aβ aggregation, but their influence on the physiological and pathological roles of APP remain unclear. We found that the D678H mutation strongly enhances amyloidogenic cleavage of APP, thus increasing the production of Aβ. This enhancement of amyloidogenic cleavage is likely because of the acceleration of APPD678H sorting into the endosomal-lysosomal pathway. In contrast, the APPD678N and APPH677R mutants do not cause the same effects. Therefore, this study indicates a regulatory role of D678H in APP sorting and processing, and provides genetic evidence for the importance of APP sorting in AD pathogenesis. The internalization of amyloid precursor protein (APP) increases its opportunity to be processed by β-secretase and to produce Amyloid-β (Aβ) that causes Alzheimer's disease (AD). We report a pathogenic APPD678H mutant that enhances APP internalization into the endosomal-lysosomal pathway and thus promotes the β-secretase cleavage and Aβ production. This study provides genetic evidence for the importance of APP sorting in AD pathogenesis. © 2014 International Society for Neurochemistry.

  4. Matrix Metalloproteinase-2 Activity is Associated with Divergent Regulation of Calponin-1 in Conductance and Resistance Arteries in Hypertension-induced Early Vascular Dysfunction and Remodelling.

    Science.gov (United States)

    Parente, Juliana M; Pereira, Camila A; Oliveira-Paula, Gustavo H; Tanus-Santos, José E; Tostes, Rita C; Castro, Michele M

    2017-10-01

    Matrix metalloproteinase (MMP)-2 participates in hypertension-induced maladaptive vascular remodelling by degrading extra- and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMCs) lead to increased cellular migration and proliferation. As calponin-1 degradation by MMP-2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP-2 activity contributes to early hypertension-induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin-1. The main objective was to analyse whether MMP-2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two-kidney, one-clip (2K-1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure was increased in 2K-1C rats, and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP-2 activity and expression were increased in both arteries, and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K-1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K-1C rats, and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K-1C rats was increased, and doxycycline decreased it. Whereas calponin-1 expression was increased in 2K-1C mesenteric arteries, calponin-1 was reduced in aortas. Doxycycline treatment reverted changes in calponin-1 expression. MMP-2 contributes to hypertrophic remodelling in aortas by decreasing calponin-1 levels, which may result in VSMC proliferation. On the other hand, MMP-2-dependent increased calponin-1 in mesenteric arteries may contribute to vascular hypercontractility in 2K-1C rats. Divergent

  5. MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways-Novel Insight into the Origins of Enamel Pathologies.

    Science.gov (United States)

    Yin, Kaifeng; Lin, Wenting; Guo, Jing; Sugiyama, Toshihiro; Snead, Malcolm L; Hacia, Joseph G; Paine, Michael L

    2017-03-13

    Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3'-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI.

  6. Corynoxeine isolated from the hook of Uncaria rhynchophylla inhibits rat aortic vascular smooth muscle cell proliferation through the blocking of extracellular signal regulated kinase 1/2 phosphorylation.

    Science.gov (United States)

    Kim, Tack-Joong; Lee, Ju-Hyun; Lee, Jung-Jin; Yu, Ji-Yeon; Hwang, Bang-Yeon; Ye, Sang-Kyu; Shujuan, Li; Gao, Li; Pyo, Myoung-Yun; Yun, Yeo-Pyo

    2008-11-01

    The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. Uncaria rhynchophylla is traditional Chinese herb that has been applied to the treatment of convulsive disorders, such as epilepsy, in China. In the present study, we examined whether corynoxeine exerts inhibitory effects on platelet-derived growth factor (PDGF)-BB-induced rat aortic VSMC proliferation and the possible mechanism of such effects. Pre-treatment of VSMCs with corynoxeine (5-50 microM) for 24 h resulted in significant decreases in cell number without any cytotoxicity; the inhibition percentages were 25.0+/-12.5, 63.0+/-27.5 and 88.0+/-12.5% at 5, 20 and 50 microM, respectively. Also, corynoxeine significantly inhibited the 50 ng/ml PDGF-BB-induced DNA synthesis of VSMCs in a concentration-dependent manner without any cytotoxicity; the inhibitions were 32.8+/-11.0, 51.8+/-8.0 and 76.9+/-7.4% at concentrations of 5, 20 and 50 microM, respectively. Pre-incubation of VSMCs with corynoxeine significantly inhibited PDGF-BB-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, whereas corynoxeine had no effects on mitogen-activated protein kinase (MAPK/ERK)-activating kinase 1 and 2 (MEK1/2), Akt, or phospholipase C (PLC)gamma1 activation or on PDGF receptor beta (PDGF-Rbeta) phosphorylation. These results suggest that corynoxeine is a potent ERK1/2 inhibitor of key PDGF-BB-induced VSMC proliferation and may be useful in the prevention and treatment of vascular diseases and restenosis after angioplasty.

  7. MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes

    International Nuclear Information System (INIS)

    Wang, Jie; Yan, Cheng-Hui; Li, Yang; Xu, Kai; Tian, Xiao-Xiang; Peng, Cheng-Fei; Tao, Jie; Sun, Ming-Yu; Han, Ya-Ling

    2013-01-01

    Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. The cellular repressor of E1A-stimulated genes (CREG) has been shown to play an important role in phenotypic modulation of VSMCs. However, the mechanism regulating CREG upstream signaling remains unclear. MicroRNAs (miRNAs) have recently been found to play a critical role in cell differentiation via target-gene regulation. This study aimed to identify a miRNA that binds directly to CREG, and may thus be involved in CREG-mediated VSMC phenotypic modulation. Computational analysis indicated that miR-31 bound to the CREG mRNA 3′ untranslated region (3′-UTR). miR-31 was upregulated in quiescent differentiated VSMCs and downregulated in proliferative cells stimulated by platelet-derived growth factor and serum starvation, demonstrating a negative relationship with the VSMC differentiation marker genes, smooth muscle α-actin, calponin and CREG. Using gain-of-function and loss-of-function approaches, CREG and VSMC differentiation marker gene expression levels were shown to be suppressed by a miR-31 mimic, but increased by a miR-31 inhibitor at both protein and mRNA levels. Notably, miR-31 overexpression or inhibition affected luciferase expression driven by the CREG 3′-UTR containing the miR-31 binding site. Furthermore, miR-31-mediated VSMC phenotypic modulation was inhibited in CREG-knockdown human VSMCs. We also determined miR-31 levels in the serum of patients with coronary artery disease (CAD), with or without in stent restenosis and in healthy controls. miR-31 levels were higher in the serum of CAD patients with restenosis compared to CAD patients without restenosis and in healthy controls. In summary, these data demonstrate that miR-31 not only directly binds to its target gene CREG and modulates the VSMC phenotype through this interaction, but also can be an important biomarker in diseases involving VSMC

  8. Vascular Contributions to Cognitive Impairment and Dementia

    Science.gov (United States)

    Gorelick, Philip B.; Scuteri, Angelo; Black, Sandra E.; DeCarli, Charles; Greenberg, Steven M.; Iadecola, Costantino; Launer, Lenore J.; Laurent, Stephane; Lopez, Oscar L.; Nyenhuis, David; Petersen, Ronald C.; Schneider, Julie A.; Tzourio, Christophe; Arnett, Donna K.; Bennett, David A.; Chui, Helena C.; Higashida, Randall T.; Lindquist, Ruth; Nilsson, Peter M.; Roman, Gustavo C.; Sellke, Frank W.; Seshadri, Sudha

    2013-01-01

    dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people. Conclusions Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative

  9. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose.

    Science.gov (United States)

    Berrone, Elena; Beltramo, Elena; Solimine, Carmela; Ape, Alessandro Ubertalli; Porta, Massimo

    2006-04-07

    Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the polyol pathway, the key enzyme of which, aldose reductase, transforms d-glucose into d-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the polyol pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 mumol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct polyol pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the polyol pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.

  10. Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosis.

    Science.gov (United States)

    Huang, Xiao X; McCaughan, Geoffrey W; Shackel, Nicholas A; Gorrell, Mark D

    2007-09-01

    Cirrhosis can lead to hepatocellular carcinoma (HCC). Non-diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared. Proliferation pathway genes, immune response genes and oncogenes were analysed by a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunostaining. Real-time RT-PCR showed up-regulation of genes in HCV cirrhosis including the proliferation-associated genes bone morphogenetic protein 3 (BMP3), placental growth factor 3 (PGF3), vascular endothelial growth factor receptor 1 (VEGFR1) and soluble VEGFR1, the oncogene FYN, and the immune response-associated genes toll-like receptor 9 (TLR9) and natural killer cell transcript 4 (NK4). Expressions of TLR2 and the oncogenes B-cell CLL/lymphoma 9 (BCL9) and PIM2 were decreased in HCV cirrhosis. In addition, PIM2 and TLR2 were increased in HCV cirrhosis with HCC compared with HCV cirrhosis. The ligand/receptor pair PGF and VEGFR1 was intensely expressed by the portal tract vascular endothelium. VEGFR1 was expressed in reactive biliary epithelial structures in fibrotic septum and in some stellate cells and macrophages. PGF and VEGFR1 may have an important role in the pathogenesis of the neovascular response in cirrhosis.

  11. Down-regulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor by HEXIM1 attenuates myocardial angiogenesis in hypoxic mice.

    Science.gov (United States)

    Yoshikawa, Noritada; Shimizu, Noriaki; Ojima, Hidenori; Kobayashi, Hiroshi; Hosono, Osamu; Tanaka, Hirotoshi

    2014-10-24

    Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF-1α and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1α protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1α and VEGF in the myocardium under hypoxic condition. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Tongqiao Huoxue Decoction ameliorates learning and memory defects in rats with vascular dementia by up-regulating the Ca(2+)-CaMKII-CREB pathway.

    Science.gov (United States)

    Ge, Chao-Liang; Wang, Xin-Ming; Huang, Zhao-Gang; Xia, Quan; Wang, Ning; Xu, Du-Juan

    2015-11-01

    The present study was aimed at determining the effects of Tongqiao Huoxue Decoction (TQHXD) on the Ca(2+)-CaMKII-CREB pathway and the memory and learning capacities of rats with vascular dementia (VD). The rat VD model was established by using an improved bilateral carotid artery ligation method. The Morris water maze experiment was used to evaluate the ethology of the VD rats following treatments with TQHXD at 3.01, 6.02, and 12.04 g·kg(-1) per day for 31 days. At the end of experiment, the hippocampus were harvested and analyzed. Western blotting and RT-PCR were used to measure the expression levels of calmodulin-binding protein kinase II(CaMKII), protein kinase A(PKA), cAMP-response element binding protein(CREB), and three N-methyl-D-aspartic acid receptor subunits (NR1, NR2A, and NR2B). Our results revealed that TQHXD could alleviate the loss of learning abilities and increase the memory capacity (P < 0.05 and P < 0.01 vs the model group, respectively). The treatment with 6.02 and 12.04 g·kg(-1) of TQHXD significantly up-regulated the Ca(2+)-CaMKII-CREB pathway in the hippocampus. In conclusion, TQHXD showed therapeutic effects on a bilateral carotid artery ligation-induced vascular dementia model, through the up-regulation of calcium signalling pathways. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  13. Acute response of circulating vascular regulating microRNAs during and after high-intensity and high-volume cycling in children

    Directory of Open Access Journals (Sweden)

    Yvonne eKilian

    2016-03-01

    Full Text Available Aim: The aim of the present study was to analyze the response of vascular circulating microRNAs (miRNAs; miR-16, miR-21, miR-126 and the VEGF mRNA following an acute bout of HIIT and HVT in children. Methods: Twelve healthy competitive young male cyclists (14.4 ± 0.8 yrs; 57.9 ± 9.4 ml·min-1·kg-1 peak oxygen uptake performed one session of high intensity 4x4 min intervals (HIIT at 90-95% peak power output, each interval separated by 3 min of active recovery, and one high volume session (HVT consisting of a constant load exercise for 90 min at 60% peak power output. Capillary blood from the earlobe was collected under resting conditions, during exercise (d1 = 20 min, d2 = 30 min, d3 = 60 min, and 0, 30, 60, 180 min after the exercise to determine miR-16, -21, -126 and VEGF mRNA.Results: HVT significantly increased miR-16 and miR-126 during and after the exercise compared to pre values, whereas HIIT showed no significant influence on the miRNAs compared to pre values. VEGF mRNA significantly increased during and after HIIT (d1, 30`, 60`, 180` and HVT (d3, 0`, 60`. Conclusion: Results of the present investigation suggest a volume dependent exercise regulation of vascular regulating miRNAs (miR-16, miR-21, miR-126 in children. In line with previous data, our data show that acute exercise can alter circulating miRNAs profiles that might be used as novel biomarkers to monitor acute and chronic changes due to exercise in various tissues.

  14. Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Hyo Jung; Ham, Sun Ah; Paek, Kyung Shin; Hwang, Jung Seok; Jung, Si Young; Kim, Min Young; Jin, Hanna; Kang, Eun Sil; Woo, Im Sun; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Han, Chang Woo; Seo, Han Geuk

    2011-01-01

    Research highlights: → Activation of PPARδ by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. → Agonist-activated PPARδ suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. → GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. → Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPARδ-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  15. Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction

    OpenAIRE

    Kumar, Santosh; Kim, Young-Rae; Vikram, Ajit; Naqvi, Asma; Li, Qiuxia; Kassan, Modar; Kumar, Vikas; Bachschmid, Markus M.; Jacobs, Julia S.; Kumar, Ajay; Irani, Kaikobad

    2017-01-01

    Many oxidative stimuli engage the 66-kDa Src homology 2 domain-containing protein (p66Shc) to induce reactive oxygen species (ROS). ROS regulated by p66Shc promotes aging and contributes to cancer, diabetes, obesity, cardiomyopathy, and atherosclerosis. Here we identify a fundamental mechanism that controls p66Shc and p66Shc-regulated ROS. We show that p66Shc is lysine acetylated when cells are faced with an oxidative stimulus (diabetes), and lysine acetylation of p66Shc is obligatory for p66...

  16. Vascular Remodeling in Experimental Hypertension

    Directory of Open Access Journals (Sweden)

    Norma R. Risler

    2005-01-01

    Full Text Available The basic hemodynamic abnormality in hypertension is an increased peripheral resistance that is due mainly to a decreased vascular lumen derived from structural changes in the small arteries wall, named (as a whole vascular remodeling. The vascular wall is an active, flexible, and integrated organ made up of cellular (endothelial cells, smooth muscle cells, adventitia cells, and fibroblasts and noncellular (extracellular matrix components, which in a dynamic way change shape or number, or reorganize in response to physiological and pathological stimuli, maintaining the integrity of the vessel wall in physiological conditions or participating in the vascular changes in cardiovascular diseases such as hypertension. Research focused on new signaling pathways and molecules that can participate in the mechanisms of vascular remodeling has provided evidence showing that vascular structure is not only affected by blood pressure, but also by mechanisms that are independent of the increased pressure. This review will provide an overview of the evidence, explaining some of the pathophysiologic mechanisms participating in the development of the vascular remodeling, in experimental models of hypertension, with special reference to the findings in spontaneously hypertensive rats as a model of essential hypertension, and in fructose-fed rats as a model of secondary hypertension, in the context of the metabolic syndrome. The understanding of the mechanisms producing the vascular alterations will allow the development of novel pharmacological tools for vascular protection in hypertensive disease.

  17. The hemodynamically-regulated vascular microenvironment promotes migration of the steroidogenic tissue during its interaction with chromaffin cells in the zebrafish embryo.

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    Chih-Wei Chou

    Full Text Available BACKGROUND: While the endothelium-organ interaction is critical for regulating cellular behaviors during development and disease, the role of blood flow in these processes is only partially understood. The dorsal aorta performs paracrine functions for the timely migration and differentiation of the sympatho-adrenal system. However, it is unclear how the adrenal cortex and medulla achieve and maintain specific integration and whether hemodynamic forces play a role. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, the possible modulation of steroidogenic and chromaffin cell integration by blood flow was investigated in the teleostean counterpart of the adrenal gland, the interrenal gland, in the zebrafish (Danio rerio. Steroidogenic tissue migration and angiogenesis were suppressed by genetic or pharmacologic inhibition of blood flow, and enhanced by acceleration of blood flow upon norepinephrine treatment. Repressed steroidogenic tissue migration and angiogenesis due to flow deficiency were recoverable following restoration of flow. The regulation of interrenal morphogenesis by blood flow was found to be mediated through the vascular microenvironment and the Fibronectin-phosphorylated Focal Adhesion Kinase (Fn-pFak signaling. Moreover, the knockdown of krüppel-like factor 2a (klf2a or matrix metalloproteinase 2 (mmp2, two genes regulated by the hemodynamic force, phenocopied the defects in migration, angiogenesis, the vascular microenvironment, and pFak signaling of the steroidogenic tissue observed in flow-deficient embryos, indicating a direct requirement of mechanotransduction in these processes. Interestingly, epithelial-type steroidogenic cells assumed a mesenchymal-like character and downregulated β-Catenin at cell-cell junctions during interaction with chromaffin cells, which was reversed by inhibiting blood flow or Fn-pFak signaling. Blood flow obstruction also affected the migration of chromaffin cells, but not through

  18. MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways–Novel Insight into the Origins of Enamel Pathologies

    Science.gov (United States)

    Yin, Kaifeng; Lin, Wenting; Guo, Jing; Sugiyama, Toshihiro; Snead, Malcolm L.; Hacia, Joseph G.; Paine, Michael L.

    2017-01-01

    Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3′-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI. PMID:28287144

  19. Novel adeno-associated viral vector delivering the utrophin gene regulator jazz counteracts dystrophic pathology in mdx mice.

    Science.gov (United States)

    Strimpakos, Georgios; Corbi, Nicoletta; Pisani, Cinzia; Di Certo, Maria Grazia; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Gabanella, Francesca; Monaco, Lucia; Mattei, Elisabetta; Passananti, Claudio

    2014-09-01

    Over-expression of the dystrophin-related gene utrophin represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). The strategy is based on the ability of utrophin to functionally replace defective dystrophin. We developed the artificial zinc finger transcription factor "Jazz" that up-regulates both the human and mouse utrophin promoter. We observed a significant recovery of muscle strength in dystrophic Jazz-transgenic mdx mice. Here we demonstrate the efficacy of an experimental gene therapy based on the systemic delivery of Jazz gene in mdx mice by adeno-associated virus (AAV). AAV serotype 8 was chosen on the basis of its high affinity for skeletal muscle. Muscle-specific expression of the therapeutic Jazz gene was enhanced by adding the muscle α-actin promoter to the AAV vector (mAAV). Injection of mAAV8-Jazz viral preparations into mdx mice resulted in muscle-specific Jazz expression coupled with up-regulation of the utrophin gene. We show a significant recovery from the dystrophic phenotype in mAAV8-Jazz-treated mdx mice. Histological and physiological analysis revealed a reduction of fiber necrosis and inflammatory cell infiltration associated with functional recovery in muscle contractile force. The combination of ZF-ATF technology with the AAV delivery can open a new avenue to obtain a therapeutic strategy for treatment of DMD. © 2014 Wiley Periodicals, Inc.

  20. Early Vascular Ageing - A Concept in Development.

    Science.gov (United States)

    M Nilsson, Peter

    2015-04-01

    Cardiovascular disease (CVD) is a prevalent condition in the elderly, often associated with metabolic disturbance and type 2 diabetes. For a number of years, research dedicated to understand atherosclerosis dominated, and for many good reasons, this pathophysiological process being proximal to the CVD events. In recent years, research has been devoted to an earlier stage of vascular pathology named arteriosclerosis (arterial stiffness) and the new concept of early vascular ageing (EVA), developed by a group of mostly European researchers. This overview describes recent developments in research dedicated to EVA and new emerging aspects found in studies of families at high cardiovascular risk. There are new aspects related to genetics, telomere biology and the role of gut microbiota. However, there is still no unifying definition available of EVA and no direct treatment, but rather only recommendations for conventional cardiovascular risk factor control. New interventions are being developed - not only new antihypertensive drugs, but also new drugs for vascular protection - the selective angiotensin-II (AT2) agonist Compound 21 (C21). Human studies are eagerly awaited. Even new functional food products could have the potential to positively influence cardiometabolic regulation, to be confirmed.

  1. Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM-1 expression via differential regulation of endoplasmic reticulum stress.

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    Ying I Wang

    Full Text Available Circulating triglyceride-rich lipoproteins (TGRL from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC, defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER stress and the unfolded protein response (UPR pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK and inositol requiring protein 1α (IRE1α, and downstream effectors including eukaryotic initiation factor-2α (eIF2α, spliced X-box-binding protein 1 (sXBP1 and C/EBP homologous protein (CHOP, directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1, a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and

  2. Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol.

    Science.gov (United States)

    Stewart, Adele; Maity, Biswanath; Anderegg, Simon P; Allamargot, Chantal; Yang, Jianqi; Fisher, Rory A

    2015-02-17

    Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6(-/-) mice consume less alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABA(B) receptors or dopamine D2 receptors partially reversed the reduction in alcohol consumption in RGS6(-/-) animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity. We propose that inhibition of RGS6 might represent a viable means to reduce alcohol cravings and withdrawal in human patients, while simultaneously protecting the heart and liver from further damage upon relapse.

  3. Vascular endothelial growth factor up-regulates the expression of intracellular adhesion molecule-1 in retinal endothelial cells via reactive oxygen species, but not nitric oxide

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-ling; WEN Liang; CHEN Yan-jiong; ZHU Yi

    2009-01-01

    Background The vascular endothelial growth factor (VEGF) is involved in the initiation of retinal vascular leakage and nonperfusion in diabetes. The intracellular adhesion molecule-1 (ICAM-1) is the key mediator of the effect of VEGFs on retinal leukostasis. Although the VEGF is expressed in an early-stage diabetic retina, whether it directly up-regulates ICAM-1 in retinal endothelial cells (ECs) is unknown. In this study, we provided a new mechanism to explain that VEGF does up-regulate the expression of ICAM-1 in retinal ECs.Methods Bovine retinal ECs (BRECs) were isolated and cultured. Immunohistochemical staining was performed to identify BRECs. The cultured cells were divided into corresponding groups. Then, VEGF (100 ng/ml) and other inhibitors were used to treat the cells. Cell lysate and the cultured supernatant were collected, and then, the protein level of ICAM-1 and phosphorylation of the endothelial nitric oxide synthase (eNOS) were detected using Western blotting. Griess reaction was used to detect nitric oxide (NO).Results Western blotting showed that the VEGF up-regulated the expression of ICAM-1 protein and increased phosphorylation of the eNOS in retinal ECs. Neither the block of NO nor protein kinase C (PKC) altered the expression of ICAM-1 or the phosphorylation of eNOS. The result of the Western blotting also showed that inhibition of phosphatidylinositol 3-kinase (PI3K) or reactive oxygen species (ROS) significantly reduced the expression of ICAM-1. Inhibition of PI3K also reduced phosphorylation of eNOS. Griess reaction showed that VEGF significantly increased during NO production. When eNOS was blocked by L-NAME or PI3K was blocked by LY294002, the basal level of NO production and the increment of NO caused by VEGF could be significantly decreased.Conclusion ROS-NO coupling in the retinal endothelium may be a new mechanism that could help to explain why VEGF induces ICAM-1 expression and the resulting leukostasis in diabetic retinopathy.

  4. A systematic expression analysis implicates Plexin-B2 and its ligand Sema4C in the regulation of the vascular and endocrine system.

    Science.gov (United States)

    Zielonka, Matthias; Xia, Jingjing; Friedel, Roland H; Offermanns, Stefan; Worzfeld, Thomas

    2010-09-10

    Plexins serve as receptors for semaphorins and play important roles in the developing nervous system. Plexin-B2 controls decisive developmental programs in the neural tube and cerebellum. However, whether Plexin-B2 also regulates biological functions in adult nonneuronal tissues is unknown. Here we show by two methodologically independent approaches that Plexin-B2 is expressed in discrete cell types of several nonneuronal tissues in the adult mouse. In the vasculature, Plexin-B2 is selectively expressed in functionally specialized endothelial cells. In endocrine organs, Plexin-B2 localizes to the pancreatic islets of Langerhans and to both cortex and medulla of the adrenal gland. Plexin-B2 expression is also detected in certain types of immune and epithelial cells. In addition, we report on a systematic comparison of the expression patterns of Plexin-B2 and its ligand Sema4C, which show complementarity or overlap in some but not all tissues. Furthermore, we demonstrate that Plexin-B2 and its family member Plexin-B1 display largely nonredundant expression patterns. This work establishes Plexin-B2 and Sema4C as potential regulators of the vascular and endocrine system and provides an anatomical basis to understand the biological functions of this ligand-receptor pair. Copyright 2010 Elsevier Inc. All rights reserved.

  5. Hydrogen sulfide potentiates interleukin-1β-induced nitric oxide production via enhancement of extracellular signal-regulated kinase activation in rat vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Jeong, Sun-Oh; Pae, Hyun-Ock; Oh, Gi-Su; Jeong, Gil-Saeng; Lee, Bok-Soo; Lee, Seoul; Kim, Du Yong; Rhew, Hyun Yul; Lee, Kang-Min; Chung, Hun-Taeg

    2006-01-01

    Hydrogen sulfide (H 2 S) and nitric oxide (NO) are endogenously synthesized from L-cysteine and L-arginine, respectively. They might constitute a cooperative network to regulate their effects. In this study, we investigated whether H 2 S could affect NO production in rat vascular smooth muscle cells (VSMCs) stimulated with interleukin-1β (IL-1β). Although H 2 S by itself showed no effect on NO production, it augmented IL-β-induced NO production and this effect was associated with increased expression of inducible NO synthase (iNOS) and activation of nuclear factor (NF)-κB. IL-1β activated the extracellular signal-regulated kinase 1/2 (ERK1/2), and this activation was also enhanced by H 2 S. Inhibition of ERK1/2 activation by the selective inhibitor U0126 inhibited IL-1β-induced NF-κB activation, iNOS expression, and NO production either in the absence or presence of H 2 S. Our findings suggest that H 2 S enhances NO production and iNOS expression by potentiating IL-1β-induced NF-κB activation through a mechanism involving ERK1/2 signaling cascade in rat VSMCs

  6. Role of Nitric Oxide Synthase on Blood Pressure Regulation and Vascular Function in Pregnant Rats on a High-Fat Diet.

    Science.gov (United States)

    Palei, Ana C; Spradley, Frank T; Granger, Joey P

    2017-03-01

    While obesity is a leading risk factor for preeclampsia, the mechanisms whereby obese women are more susceptible to pregnancy-induced hypertension are unclear. As high-fat diet (HFD) is an important contributor to the development of obesity, we tested the hypothesis that pregnant rats on HFD have hypertension and endothelial dysfunction due to reduced nitric oxide synthase (NOS). Twelve-week-old Sprague-Dawley female rats were fed normal diet (ND, 13% fat kcal) or HFD (40% fat kcal) for 9 weeks. Timed-pregnant rats were then generated and the effect of HFD on mean arterial blood pressure (MAP) and vascular function was assessed on gestational day (GD) 19. MAP was not different between HFD and ND pregnant rats. Intriguingly, sensitivity to acetylcholine-induced endothelium-dependent vasorelaxation was enhanced in small mesenteric arteries of HFD dams compared to ND controls (logEC50 -7.9 ± 0.3 vs. -6.7 ± 0.3 M; P hydrochloride (100 mg/l, drinking water) from GD 14 to 19. It was found that NOS inhibition increased MAP equally in HFD and ND groups. Contrary to our initial hypothesis, HFD dams were normotensive and presented increased endothelial function and NO/NOS3 levels. This enhanced NOS-mediated vascular function does not appear to have a major impact on blood pressure regulation of HFD-fed pregnant rats. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  7. YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells.

    Science.gov (United States)

    Bora-Singhal, Namrata; Nguyen, Jonathan; Schaal, Courtney; Perumal, Deepak; Singh, Sandeep; Coppola, Domenico; Chellappan, Srikumar

    2015-06-01

    Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional coactivator yes-associated protein 1 (YAP1), which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal, and vascular mimicry. Depleting YAP1 reduced the expression of multiple epithelial-mesenchymal transition genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression. © 2015 AlphaMed Press.

  8. Peroxisome Proliferator-Activated Receptor γ Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells

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    Yazi Huang

    2014-01-01

    Full Text Available Lipid phosphate phosphohydrolase 1 (LPP1, a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor γ (PPARγ in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR demonstrated that activation of PPARγ increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPARγ binds to the putative PPAR-responsive elements (PPREs within the 5′-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPARγ and rosiglitazone, a specific ligand for PPARγ, could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPARγ transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPARγ in the metabolism of phospholipids.

  9. Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation.

    Science.gov (United States)

    Pascoli, Vincent; Cahill, Emma; Bellivier, Frank; Caboche, Jocelyne; Vanhoutte, Peter

    2014-12-15

    Addiction is a chronic and relapsing psychiatric disorder that is thought to occur in vulnerable individuals. Synaptic plasticity evoked by drugs of abuse in the so-called neuronal circuits of reward has been proposed to underlie behavioral adaptations that characterize addiction. By increasing dopamine in the striatum, addictive drugs alter the balance of dopamine and glutamate signals converging onto striatal medium-sized spiny neurons (MSNs) and activate intracellular events involved in long-term behavioral alterations. Our laboratory contributed to the identification of salient molecular changes induced by administration of addictive drugs to rodents. We pioneered the observation that a common feature of addictive drugs is to activate, by a double tyrosine/threonine phosphorylation, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the striatum, which control a plethora of substrates, some of them being critically involved in cocaine-mediated molecular and behavioral adaptations. Herein, we review how the interplay between dopamine and glutamate signaling controls cocaine-induced ERK1/2 activation in MSNs. We emphasize the key role of N-methyl-D-aspartate receptor potentiation by D1 receptor to trigger ERK1/2 activation and its subsequent nuclear translocation where it modulates both epigenetic and genetic processes engaged by cocaine. We discuss how cocaine-induced long-term synaptic and structural plasticity of MSNs, as well as behavioral adaptations, are influenced by ERK1/2-controlled targets. We conclude that a better knowledge of molecular mechanisms underlying ERK1/2 activation by drugs of abuse and/or its role in long-term neuronal plasticity in the striatum may provide a new route for therapeutic treatment in addiction. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells*

    Science.gov (United States)

    Gizard, Florence; Zhao, Yue; Findeisen, Hannes M.; Qing, Hua; Cohn, Dianne; Heywood, Elizabeth B.; Jones, Karrie L.; Nomiyama, Takashi; Bruemmer, Dennis

    2011-01-01

    Members of the NR4A subgroup of the nuclear hormone receptor superfamily have emerged as key transcriptional regulators of proliferation and inflammation. NOR1 constitutes a ligand-independent transcription factor of this subgroup and induces cell proliferation; however, the transcriptional mechanisms underlying this mitogenic role remain to be defined. Here, we demonstrate that the F-box protein SKP2 (S phase kinase-associated protein 2), the substrate-specific receptor of the ubiquitin ligase responsible for the degradation of p27KIP1 through the proteasome pathway, constitutes a direct transcriptional target for NOR1. Mitogen-induced Skp2 expression is silenced in vascular smooth muscle cells (VSMC) isolated from Nor1-deficient mice or transfected with Nor1 siRNA. Conversely, adenovirus-mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27. Transient transfection experiments establish that NOR1 transactivates the Skp2 promoter through a nerve growth factor-induced clone B response element (NBRE). Electrophoretic mobility shift and chromatin immunoprecipitation assays further revealed that NOR1 is recruited to this NBRE site in the Skp2 promoter in response to mitogenic stimulation. In vivo Skp2 expression is increased during the proliferative response underlying neointima formation, and this transcriptional induction depends on the expression of NOR1. Finally, we demonstrate that overexpression of Skp2 rescues the proliferative arrest of Nor1-deficient VSMC. Collectively, these results characterize Skp2 as a novel NOR1-regulated target gene and detail a previously unrecognized transcriptional cascade regulating mitogen-induced VSMC proliferation. PMID:21868379

  11. Vascular cognitive impairment

    Directory of Open Access Journals (Sweden)

    N.V. Vakhnina

    2014-01-01

    Full Text Available Vascular pathology of the brain is the second most common cause of cognitive impairment after Alzheimer's disease. The article describes the modern concepts of etiology, pathogenetic mechanisms, clinical features and approaches to diagnosis and therapy of vascular cognitive impairment (VCI. Cerebrovascular accident, chronic cerebral circulatory insufficiency and their combination, sometimes in combination with a concomitant neurodegenerative process, are shown to be the major types of brain lesions leading to VCI. The clinical presentation of VCI is characterized by the neuropsychological status dominated by impairment of the executive frontal functions (planning, control, attention in combination with focal neurological symptoms. The diagnosis is based on comparing of the revealed neuropsychological and neurological features with neuroimaging data. Neurometabolic, acetylcholinergic, glutamatergic, and other vasoactive drugs and non-pharmacological methods are widely used to treat VCI. 

  12. Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis.

    Science.gov (United States)

    Zhang, Hui; Wang, Daren; Li, Min; Plecitá-Hlavatá, Lydie; D'Alessandro, Angelo; Tauber, Jan; Riddle, Suzette; Kumar, Sushil; Flockton, Amanda; McKeon, B Alexandre; Frid, Maria G; Reisz, Julie A; Caruso, Paola; El Kasmi, Karim C; Ježek, Petr; Morrell, Nicholas W; Hu, Cheng-Jun; Stenmark, Kurt R

    2017-12-19

    An emerging metabolic theory of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyperproliferative, apoptosis-resistant, proinflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) that exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the tricarboxylic acid cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that in PH-Fibs microRNA-124 (miR-124) regulates PTBP1 (polypyrimidine tract binding protein 1) expression to control alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2, resulting in an increased PKM2/PKM1 ratio, which promotes glycolysis and proliferation even in aerobic environments. Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects. PTBP1 gene knockdown was achieved via PTBP1-siRNA; restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and shikonin were used to manipulate PKM2 glycolytic function. Histone deacetylase inhibitors were used to treat cells. Metabolic products were determined by mass spectrometry-based metabolomics analyses, and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry. We detected an increased PKM2/PKM1 ratio in PH-Fibs compared with normal subjects. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation, and attenuated macrophage interleukin-1β expression. Furthermore, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, ie, lactate), rescued mitochondrial

  13. Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2

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    Crende Olatz

    2011-08-01

    Full Text Available Abstract Background Human melanoma frequently colonizes bone marrow (BM since its earliest stage of systemic dissemination, prior to clinical metastasis occurrence. However, how melanoma cell adhesion and proliferation mechanisms are regulated within bone marrow stromal cell (BMSC microenvironment remain unclear. Consistent with the prometastatic role of inflammatory and angiogenic factors, several studies have reported elevated levels of cyclooxygenase-2 (COX-2 in melanoma although its pathogenic role in bone marrow melanoma metastasis is unknown. Methods Herein we analyzed the effect of cyclooxygenase-2 (COX-2 inhibitor celecoxib in a model of generalized BM dissemination of left cardiac ventricle-injected B16 melanoma (B16M cells into healthy and bacterial endotoxin lipopolysaccharide (LPS-pretreated mice to induce inflammation. In addition, B16M and human A375 melanoma (A375M cells were exposed to conditioned media from basal and LPS-treated primary cultured murine and human BMSCs, and the contribution of COX-2 to the adhesion and proliferation of melanoma cells was also studied. Results Mice given one single intravenous injection of LPS 6 hour prior to cancer cells significantly increased B16M metastasis in BM compared to untreated mice; however, administration of oral celecoxib reduced BM metastasis incidence and volume in healthy mice, and almost completely abrogated LPS-dependent melanoma metastases. In vitro, untreated and LPS-treated murine and human BMSC-conditioned medium (CM increased VCAM-1-dependent BMSC adherence and proliferation of B16M and A375M cells, respectively, as compared to basal medium-treated melanoma cells. Addition of celecoxib to both B16M and A375M cells abolished adhesion and proliferation increments induced by BMSC-CM. TNFα and VEGF secretion increased in the supernatant of LPS-treated BMSCs; however, anti-VEGF neutralizing antibodies added to B16M and A375M cells prior to LPS-treated BMSC-CM resulted in a

  14. βENaC acts as a mechanosensor in renal vascular smooth muscle cells that contributes to renal myogenic blood flow regulation, protection from renal injury and hypertension.

    Science.gov (United States)

    Drummond, Heather A; Stec, David E

    2015-06-01

    Pressure-induced constriction (also known as the "myogenic response") is an important mechanodependent response in small renal arteries and arterioles. The response is initiated by vascular smooth muscle cell (VSMC) stretch due to an increase in intraluminal pressure and leads to vasoconstriction. The myogenic response has two important roles as a mechanism of local blood flow autoregulation and protection against systemic blood pressure-induced microvascular damage. However, the molecular mechanisms underlying initiation of myogenic response are unresolved. Although several molecules have been considered initiators of the response, our laboratory has focused on the role of degenerin proteins because of their strong evolutionary link to mechanosensing in the nematode. Our laboratory has addressed the hypothesis that certain degenerin proteins act as mechanosensors in VSMCs. This article discusses the importance of a specific degenerin protein, β Epithelial Na + Channel (βENaC), in pressure-induced vasoconstriction, renal blood flow and susceptibility to renal injury. We propose that loss of the renal myogenic constrictor response delays the correction of renal blood flow that occurs with fluctuations in systemic pressure, which allows pressure swings to be transmitted to the microvasculature, thus increasing the susceptibility to renal injury and hypertension. The role of βENaC in myogenic regulation is independent of tubular βENaC and thus represents a non-tubular role for βENaC in renal-cardiovascular homeostasis.

  15. Aqueous extract of Allium sativum L bulbs offer nephroprotection by attenuating vascular endothelial growth factor and extracellular signal-regulated kinase-1 expression in diabetic rats.

    Science.gov (United States)

    Shiju, T M; Rajkumar, R; Rajesh, N G; Viswanathan, Pragasam

    2013-02-01

    To investigate the nephroprotective effect of garlic and elucidate the mechanism by which it prevents the progression of diabetic nephropathy in diabetic rats, diabetes was induced by a single ip injection of streptozotocin (45 mg/kg body weight). Garlic extract (500 mg/kg body weight) and aminoguanidine (1 g/L) were supplemented in the treatment groups. Histopathological examination using H&E, PAS staining and the immunohistochemical analysis of vascular endothelial growth factor (VEGF) and extracellular signal-regulated kinase-1 (ERK-1) expression were performed on kidney sections at the end of 12 weeks. Significant change in both, the urine and serum biochemistry confirmed kidney damage in diabetic animals which was further confirmed by the histological changes such as mesangial expansion, glomerular basement membrane thickening, glycosuria and proteinuria. However, the diabetic animals treated with garlic extract showed a significant change in urine and serum biochemical parameters such as albumin, urea nitrogen and creatinine compared to that of diabetic rats. Further, the garlic supplemented diabetic rats showed a significant decrease in the expression of VEGF and ERK-1 compared to diabetic rats, attenuating mesangial expansion and glomerulosclerosis. Thus, garlic extract rendered nephroprotection in diabetic rats.

  16. CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells.

    Science.gov (United States)

    Liu, Guan-Ting; Huang, Yuan-Li; Tzeng, Huey-En; Tsai, Chun-Hao; Wang, Shih-Wei; Tang, Chih-Hsin

    2015-02-28

    Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR-199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo. Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR-199a. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. The Phosphatase PTP-PEST/PTPN12 Regulates Endothelial Cell Migration and Adhesion, but Not Permeability, and Controls Vascular Development and Embryonic Viability*

    Science.gov (United States)

    Souza, Cleiton Martins; Davidson, Dominique; Rhee, Inmoo; Gratton, Jean-Philippe; Davis, Elaine C.; Veillette, André

    2012-01-01

    Protein-tyrosine phosphatase (PTP)-PEST (PTPN12) is ubiquitously expressed. It is essential for normal embryonic development and embryonic viability in mice. Herein we addressed the involvement of PTP-PEST in endothelial cell functions using a combination of genetic and biochemical approaches. By generating primary endothelial cells from an inducible PTP-PEST-deficient mouse, we found that PTP-PEST is not needed for endothelial cell differentiation and proliferation or for the control of endothelial cell permeability. Nevertheless, it is required for integrin-mediated adhesion and migration of endothelial cells. PTP-PEST-deficient endothelial cells displayed increased tyrosine phosphorylation of Cas, paxillin, and Pyk2, which were previously also implicated in integrin functions. By eliminating PTP-PEST in endothelial cells in vivo, we obtained evidence that expression of PTP-PEST in endothelial cells is required for normal vascular development and embryonic viability. Therefore, PTP-PEST is a key regulator of integrin-mediated functions in endothelial cells seemingly through its capacity to control Cas, paxillin, and Pyk2. This function explains at least in part the essential role of PTP-PEST in embryonic development and viability. PMID:23105101

  18. Regulation of glucose transporter protein-1 and vascular endothelial growth factor by hypoxia inducible factor 1α under hypoxic conditions in Hep-2 human cells.

    Science.gov (United States)

    Xu, Ou; Li, Xiaoming; Qu, Yongtao; Liu, Shuang; An, Jie; Wang, Maoxin; Sun, Qingjia; Zhang, Wen; Lu, Xiuying; Pi, Lihong; Zhang, Min; Shen, Yupeng

    2012-12-01

    The present study evaluated the regulation of glucose transporter protein-1 (Glut-1) and vascular endothelial growth factor (VEGF) by hypoxia inducible factor 1α (HIF-1α) under hypoxic conditions in Hep-2 human cells to explore the feasibility of these three genes as tumor markers. Hep-2 cells were cultured under hypoxic and normoxic conditions for 6, 12, 24, 36 and 48 h. The proliferation of Hep-2 cells was evaluated using an MTT assay. The protein and mRNA expression levels of HIF-1α, Glut-1 and VEGF were detected using the S-P immunocytochemical method, western blotting and reverse transcription polymerase chain reaction (RT-PCR). The results revealed that the expression levels of HIF-1α, Glut-1 and VEGF protein in Hep-2 cells were significantly elevated under hypoxic conditions compared with those under normoxic conditions over 36 h. Under hypoxic conditions, mRNA levels of HIF-1α were stable, while mRNA levels of Glut-1 and VEGF changed over time. In conclusion, Glut-1 and VEGF were upregulated by HIF-1α under hypoxic conditions in a time-dependent manner in Hep-2 cells and their co-expression serves as a tumor marker.

  19. Diabetes diminishes the portal-systemic collateral vascular response to vasopressin via vasopressin receptor and Gα proteins regulations in cirrhotic rats.

    Directory of Open Access Journals (Sweden)

    Jing-Yi Lee

    Full Text Available Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL-induced cirrhosis received vehicle (citrate buffer or streptozotocin (diabetic, BDL/STZ. The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist and overcome by NaF (a G protein activator. The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.

  20. Glycogen synthase kinase 3β regulation of nuclear factor of activated T-cells isoform c1 in the vascular smooth muscle cell response to injury

    International Nuclear Information System (INIS)

    Chow Winsion; Hou Guangpei; Bendeck, Michelle P.

    2008-01-01

    The migration and proliferation of vascular smooth muscle cells (vSMCs) are critical events in neointima formation during atherosclerosis and restenosis. The transcription factor nuclear factor of activated T-cells-isoform c1 (NFATc1) is regulated by atherogenic cytokines, and has been implicated in the migratory and proliferative responses of vSMCs through the regulation of gene expression. In T-cells, calcineurin de-phosphorylates NFATc1, leading to its nuclear import, while glycogen synthase kinase 3 β (GSK3β) phosphorylates NFATc1 and promotes its nuclear export. However, the relationship between NFATc1 and GSK3β has not been studied during SMC migration and proliferation. We investigated this by scrape wounding vSMCs in vitro, and studying wound repair. NFATc1 protein was transiently increased, reaching a peak at 8 h after wounding. Cell fractionation and immunocytochemistry revealed that NFATc1 accumulation in the nucleus was maximal at 4 h after injury, and this was coincident with a significant 9 fold increase in transcriptional activity. Silencing NFATc1 expression with siRNA or inhibition of NFAT with cyclosporin A (CsA) attenuated wound closure by vSMCs. Phospho-GSK3β (inactive) increased to a peak at 30 min after injury, preceding the nuclear accumulation of NFATc1. Overexpression of a constitutively active mutant of GSK3β delayed the nuclear accumulation of NFATc1, caused a 50% decrease in NFAT transcriptional activity, and attenuated vSMC wound repair. We conclude that NFATc1 promotes the vSMC response to injury, and that inhibition of GSK3β is required for the activation of NFAT during wound repair

  1. The primary vascular dysregulation syndrome: implications for eye diseases

    Science.gov (United States)

    2013-01-01

    Vascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We distinguish primary vascular dysregulation (PVD, formerly called vasospastic syndrome) and secondary vascular dysregulation (SVD). Subjects with PVD tend to have cold extremities, low blood pressure, reduced feeling of thirst, altered drug sensitivity, increased pain sensitivity, prolonged sleep onset time, altered gene expression in the lymphocytes, signs of oxidative stress, slightly increased endothelin-1 plasma level, low body mass index and often diffuse and fluctuating visual field defects. Coldness, emotional or mechanical stress and starving can provoke symptoms. Virtually all organs, particularly the eye, can be involved. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased. Subjects with PVD have increased risk for normal-tension glaucoma, optic nerve compartment syndrome, central serous choroidopathy, Susac syndrome, retinal artery and vein occlusions and anterior ischaemic neuropathy without atherosclerosis. Further characteristics are their weaker blood–brain and blood-retinal barriers and the higher prevalence of optic disc haemorrhages and activated astrocytes. Subjects with PVD tend to suffer more often from tinnitus, muscle cramps, migraine with aura and silent myocardial ischaemic and are at greater risk for altitude sickness. While the main cause of vascular dysregulation is vascular endotheliopathy, dysfunction of the autonomic nervous system is also involved. In contrast, SVD occurs in the context of other diseases such as multiple sclerosis, retrobulbar neuritis, rheumatoid arthritis, fibromyalgia and giant cell arteritis. Taking into consideration the high prevalence of PVD in the population and potentially linked pathologies, in the current article, the authors provide

  2. IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model.

    Science.gov (United States)

    Lorenc, Valeria E; Subirada Caldarone, Paula V; Paz, María C; Ferrer, Darío G; Luna, José D; Chiabrando, Gustavo A; Sánchez, María C

    2018-02-01

    In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.

  3. Vascular disease in cocaine addiction.

    Science.gov (United States)

    Bachi, Keren; Mani, Venkatesh; Jeyachandran, Devi; Fayad, Zahi A; Goldstein, Rita Z; Alia-Klein, Nelly

    2017-07-01

    Cocaine, a powerful vasoconstrictor, induces immune responses including cytokine elevations. Chronic cocaine use is associated with functional brain impairments potentially mediated by vascular pathology. Although the Crack-Cocaine epidemic has declined, its vascular consequences are increasingly becoming evident among individuals with cocaine use disorder of that period, now aging. Paradoxically, during the period when prevention efforts could make a difference, this population receives psychosocial treatment at best. We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. PubMed and Academic Search Complete were used with relevant terms. Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. The etiology underlying cocaine's acute and chronic vascular effects is multifactorial, spanning hypertension, impaired homeostasis and platelet function, thrombosis, thromboembolism, and alterations in blood flow. Early detection of vascular disease in cocaine addiction by multimodality imaging is discussed. Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding β-blockers. Given the vascular toxicity cocaine induces, further compounded by smoking and alcohol comorbidity, and interacting with aging of the crack generation, there is a public health imperative to identify pre-symptomatic markers of vascular impairments in cocaine addiction and employ preventive treatment to reduce silent disease progression. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. [Pathological gambling].

    Science.gov (United States)

    Dembinsky, Yael; Iancu, Iulian; Dannon, Pinhas

    2007-10-01

    Gambling behaviour is well-known for many centuries and is growing in popularity and frequency. Its etiology is multi-factorial and in this paper we review new developments in the field of pathological gambling, both regarding etiology and treatment progress. The aim of this review is to increase the physicians' awareness towards this entity.

  5. Tc and R M encephalic: normal and pathological patterns

    International Nuclear Information System (INIS)

    Servente, L.

    2012-01-01

    This presentation is about the basic concepts of CT and MR encephalic: The physical principles and the use of iodine allow to detect neoplasms, infections, vascular alterations and inflammation. CT is essential in traumatic pathology to discard possible bleeding, CT angiography, tumor pathology and infections, calcifications and osseous lesions, secondary indications, pathology of cranial pairs, epilepsy, encephalitis, etc.

  6. VASCULAR SURGERY

    African Journals Online (AJOL)

    2016-06-02

    Jun 2, 2016 ... with the literature from South Africa over the last four decades, and reflects the high rate of interpersonal violence in the country.14,15 As expected, cervical ... via the intact circle of Willis in young patients is the most likely explanation for the lack of strokes. Five patients were referred to the Durban vascular ...

  7. Vascular Disorders

    Science.gov (United States)

    ... All Topics A-Z Videos Infographics Symptom Picker Anatomy Bones Joints Muscles Nerves Vessels Tendons About Hand Surgery What is a Hand Surgeon? What is a Hand Therapist? Media Find a Hand Surgeon Home Anatomy Vascular Disorders Email to a friend * required fields ...

  8. Aspirin-induced AMP-activated protein kinase activation regulates the proliferation of vascular smooth muscle cells from spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Sung, Jin Young; Choi, Hyoung Chul

    2011-01-01

    Highlights: → Aspirin-induced AMPK phosphorylation was greater in VSMC from SHR than WKY. → Aspirin-induced AMPK phosphorylation inhibited proliferation of VSMC from SHR. → Low basal AMPK phosphorylation in SHR elicits increased VSMC proliferation. → Inhibition of AMPK restored decreased VSMC proliferation by aspirin in SHR. → Aspirin exerts anti-proliferative effect through AMPK activation in VSMC from SHR. -- Abstract: Acetylsalicylic acid (aspirin), used to reduce risk of cardiovascular disease, plays an important role in the regulation of cellular proliferation. However, mechanisms responsible for aspirin-induced growth inhibition are not fully understood. Here, we investigated whether aspirin may exert therapeutic effects via AMP-activated protein kinase (AMPK) activation in vascular smooth muscle cells (VSMC) from wistar kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aspirin increased AMPK and acetyl-CoA carboxylase phosphorylation in a time- and dose-dependent manner in VSMCs from WKY and SHR, but with greater efficacy in SHR. In SHR, a low basal phosphorylation status of AMPK resulted in increased VSMC proliferation and aspirin-induced AMPK phosphorylation inhibited proliferation of VSMCs. Compound C, an AMPK inhibitor, and AMPK siRNA reduced the aspirin-mediated inhibition of VSMC proliferation, this effect was more pronounced in SHR than in WKY. In VSMCs from SHR, aspirin increased p53 and p21 expression and inhibited the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. These results indicate that in SHR VSMCs aspirin exerts anti-proliferative effects through the induction of AMPK phosphorylation.

  9. Aspirin-induced AMP-activated protein kinase activation regulates the proliferation of vascular smooth muscle cells from spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Jin Young [Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2011-05-06

    Highlights: {yields} Aspirin-induced AMPK phosphorylation was greater in VSMC from SHR than WKY. {yields} Aspirin-induced AMPK phosphorylation inhibited proliferation of VSMC from SHR. {yields} Low basal AMPK phosphorylation in SHR elicits increased VSMC proliferation. {yields} Inhibition of AMPK restored decreased VSMC proliferation by aspirin in SHR. {yields} Aspirin exerts anti-proliferative effect through AMPK activation in VSMC from SHR. -- Abstract: Acetylsalicylic acid (aspirin), used to reduce risk of cardiovascular disease, plays an important role in the regulation of cellular proliferation. However, mechanisms responsible for aspirin-induced growth inhibition are not fully understood. Here, we investigated whether aspirin may exert therapeutic effects via AMP-activated protein kinase (AMPK) activation in vascular smooth muscle cells (VSMC) from wistar kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aspirin increased AMPK and acetyl-CoA carboxylase phosphorylation in a time- and dose-dependent manner in VSMCs from WKY and SHR, but with greater efficacy in SHR. In SHR, a low basal phosphorylation status of AMPK resulted in increased VSMC proliferation and aspirin-induced AMPK phosphorylation inhibited proliferation of VSMCs. Compound C, an AMPK inhibitor, and AMPK siRNA reduced the aspirin-mediated inhibition of VSMC proliferation, this effect was more pronounced in SHR than in WKY. In VSMCs from SHR, aspirin increased p53 and p21 expression and inhibited the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. These results indicate that in SHR VSMCs aspirin exerts anti-proliferative effects through the induction of AMPK phosphorylation.

  10. Mechanism by which nuclear factor-kappa beta (NF-kB regulates ovine fetal pulmonary vascular smooth muscle cell proliferation

    Directory of Open Access Journals (Sweden)

    Uchenna D. Ogbozor

    2015-09-01

    Full Text Available Platelet activating factor (PAF modulates ovine fetal pulmonary hemodynamic. PAF acts through its receptors (PAFR in pulmonary vascular smooth muscle cells (PVSMC to phosphorylate and induce nuclear translocation of NF-kB p65 leading to PVSMC proliferation. However, the interaction of NF-kB p65 and PAF in the nuclear domain to effect PVSMC cell growth is not clearly defined. We used siRNA-dependent translation initiation arrest to study a mechanism by which NF-kB p65 regulates PAF stimulation of PVSMC proliferation. Our hypotheses are: (a PAF induces NF-kB p65 DNA binding and (b NF-kB p65 siRNA attenuates PAF stimulation of PVSMC proliferation. For DNA binding, cells were fed 10 nM PAF with and without PAFR antagonists WEB 2170, CV 3988 or BN 52021 and incubated for 12 h. DNA binding was measured by specific ELISA. For NF-kB p65 siRNA effect, starved cells transfected with the siRNA were incubated for 24 h with and without 10 nM PAF. Cell proliferation was measured by DNA synthesis while expression of NF-kB p65 and PAFR protein was measured by Western blotting. In both studies, the effect of 10% FBS alone was used as the positive control. In general, PAF stimulated DNA binding which was inhibited by PAFR antagonists. siRNAs to NF-kB p65 and PAFR significantly attenuated cell proliferation compared to 10% FBS and PAF effect. Inclusion of PAF in siRNA-treated cells did not reverse inhibitory effect of NF-kB p65 siRNA on DNA synthesis. PAFR expression was inhibited in siRNA-treated cells. These data show that PAF-stimulation of PVSMC proliferation occurs via a PAFR-NF-kB p65 linked pathway.

  11. Vascular endothelial growth factor C promotes cervical cancer metastasis via up-regulation and activation of RhoA/ROCK-2/moesin cascade

    International Nuclear Information System (INIS)

    He, Mian; Cheng, Yang; Li, Wen; Liu, Qiongshan; Liu, Junxiu; Huang, Jinghe; Fu, Xiaodong

    2010-01-01

    The elevated expression of vascular endothelial growth factor C (VEGF-C) is correlated with clinical cervical cancer metastasis and patient survival, which is interpreted by VEGF-C functions to stimulate angiogenesis and lymphatic genesis. However, the direct impact of VEGF-C on cervical cancer cell motility remains largely unknown. In this study, we investigated the effects of VEGF-C on actin cytoskeleton remodeling and on cervical cancer cell migration and invasion and how the actin-regulatory protein, moesin regulated these effects through RhoA/ROCK-2 signaling pathway. On cervical carcinoma cell line SiHa cells, exposure of VEGF-C triggered remodeling of the actin cytoskeleton and the formation of membrane ruffles, which was required for cell movement. VEGF-C significantly enhanced SiHa cells horizontal migration and three-dimensional invasion into matrices. These actions were dependent on increased expression and phosphorylation of the actin-regulatory protein moesin and specific moesin siRNA severely impaired VEGF-C stimulated-cell migration. The extracellular small GTPase RhoA/ROCK-2 cascade mediated the increased moesin expression and phosphorylation, which was discovered by the use of Y-27632, a specific inhibitor of Rho kinase and by transfected constitutively active, dominant-negative RhoA as well as ROCK-2 SiRNA. Furthermore, in the surgical cervical specimen from the patients with FIGO stage at cervical intra-epithelial neoplasia and I-II cervical squamous cell carcinoma, the expression levels of moesin were found to be significantly correlated with tumor malignancy and metastasis. These results implied that VEGF-C promoted cervical cancer metastasis by upregulation and activation of moesin protein through RhoA/ROCK-2 pathway. Our findings offer new insight into the role of VEGF-C on cervical cancer progression and may provide potential targets for cervical cancer therapy

  12. Vascular endothelial growth factor C promotes cervical cancer metastasis via up-regulation and activation of RhoA/ROCK-2/moesin cascade

    Directory of Open Access Journals (Sweden)

    Huang Jinghe

    2010-04-01

    Full Text Available Abstract Background The elevated expression of vascular endothelial growth factor C (VEGF-C is correlated with clinical cervical cancer metastasis and patient survival, which is interpreted by VEGF-C functions to stimulate angiogenesis and lymphatic genesis. However, the direct impact of VEGF-C on cervical cancer cell motility remains largely unknown. Methods In this study, we investigated the effects of VEGF-C on actin cytoskeleton remodeling and on cervical cancer cell migration and invasion and how the actin-regulatory protein, moesin regulated these effects through RhoA/ROCK-2 signaling pathway. Results On cervical carcinoma cell line SiHa cells, exposure of VEGF-C triggered remodeling of the actin cytoskeleton and the formation of membrane ruffles, which was required for cell movement. VEGF-C significantly enhanced SiHa cells horizontal migration and three-dimensional invasion into matrices. These actions were dependent on increased expression and phosphorylation of the actin-regulatory protein moesin and specific moesin siRNA severely impaired VEGF-C stimulated-cell migration. The extracellular small GTPase RhoA/ROCK-2 cascade mediated the increased moesin expression and phosphorylation, which was discovered by the use of Y-27632, a specific inhibitor of Rho kinase and by transfected constitutively active, dominant-negative RhoA as well as ROCK-2 SiRNA. Furthermore, in the surgical cervical specimen from the patients with FIGO stage at cervical intra-epithelial neoplasia and I-II cervical squamous cell carcinoma, the expression levels of moesin were found to be significantly correlated with tumor malignancy and metastasis. Conclusions These results implied that VEGF-C promoted cervical cancer metastasis by upregulation and activation of moesin protein through RhoA/ROCK-2 pathway. Our findings offer new insight into the role of VEGF-C on cervical cancer progression and may provide potential targets for cervical cancer therapy.

  13. Mechanism by which nuclear factor-kappa beta (NF-kB) regulates ovine fetal pulmonary vascular smooth muscle cell proliferation.

    Science.gov (United States)

    Ogbozor, Uchenna D; Opene, Michael; Renteria, Lissette S; McBride, Shaemion; Ibe, Basil O

    2015-09-01

    Platelet activating factor (PAF) modulates ovine fetal pulmonary hemodynamic. PAF acts through its receptors (PAFR) in pulmonary vascular smooth muscle cells (PVSMC) to phosphorylate and induce nuclear translocation of NF-kB p65 leading to PVSMC proliferation. However, the interaction of NF-kB p65 and PAF in the nuclear domain to effect PVSMC cell growth is not clearly defined. We used siRNA-dependent translation initiation arrest to study a mechanism by which NF-kB p65 regulates PAF stimulation of PVSMC proliferation. Our hypotheses are: (a) PAF induces NF-kB p65 DNA binding and (b) NF-kB p65 siRNA attenuates PAF stimulation of PVSMC proliferation. For DNA binding, cells were fed 10 nM PAF with and without PAFR antagonists WEB 2170, CV 3988 or BN 52021 and incubated for 12 h. DNA binding was measured by specific ELISA. For NF-kB p65 siRNA effect, starved cells transfected with the siRNA were incubated for 24 h with and without 10 nM PAF. Cell proliferation was measured by DNA synthesis while expression of NF-kB p65 and PAFR protein was measured by Western blotting. In both studies, the effect of 10% FBS alone was used as the positive control. In general, PAF stimulated DNA binding which was inhibited by PAFR antagonists. siRNAs to NF-kB p65 and PAFR significantly attenuated cell proliferation compared to 10% FBS and PAF effect. Inclusion of PAF in siRNA-treated cells did not reverse inhibitory effect of NF-kB p65 siRNA on DNA synthesis. PAFR expression was inhibited in siRNA-treated cells. These data show that PAF-stimulation of PVSMC proliferation occurs via a PAFR-NF-kB p65 linked pathway.

  14. [Dual pathology].

    Science.gov (United States)

    Rougier, A

    2008-05-01

    Dual pathology is defined as the association of two potentially epileptogenic lesions, hippocampal (sclerosis, neuronal loss) and extrahippocampal (temporal or extratemporal). Epileptic activity may be generated by either lesion and the relative importance of every lesion's epileptogenicity conditions the surgical strategy adopted. Most frequently associated with hippocampal sclerosis are cortical dysplasias. The common physiopathology of the two lesions is not clearly established. Extrahippocampal lesions may be undetectable on MRI (microdysgenesis, for example) and ictal discharge patterns may vary among dual pathology patients. The surgical strategy depends on the location of the extrahippocampal lesion and its relative role in seizure generation; however, reported surgical results suggest that simultaneous resection of mesial temporal structures along with the extrahippocampal lesion should be performed.

  15. Microglial pathology

    OpenAIRE

    Streit, Wolfgang J; Xue, Qing-Shan; Tischer, Jasmin; Bechmann, Ingo

    2014-01-01

    This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer’s disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial ...

  16. Interferon Regulator Factor 8 (IRF8 Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells.

    Directory of Open Access Journals (Sweden)

    Lin Sun

    Full Text Available Interferon Regulatory Factor-8 (IRF8 is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1 infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8+ T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8+ T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye.

  17. Limb vascular function in women

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Gliemann, Lasse

    2018-01-01

    Throughout life, women are subjected to both acute fluctuations in sex hormones, associated with the menstrual cycle, and chronic changes following the onset of menopause. Female sex hormones, and in particular estrogen, strongly influence cardiovascular function such as the regulation of vascular...... studies. Physical activity should be recommended for women of all ages, but the most essential timing for maintenance of vascular health may be from menopause and onwards....

  18. Non-vascular surgical mediastinum

    International Nuclear Information System (INIS)

    Schiavon, S.; Trenaghi, P.; Nardini, S.; Pagan, V.

    1989-01-01

    A review was made of the chest X-ray features of 120 patients who underwent surgical treatment for mediastinal non-vascular pathologies over the past 12 years in the Mestre Hospital. A method of analysis is proposed which takes into account not only the differences between the immediate post-operative period and the follow-up, but also the anatomotopographic partition and the surgical practice. Normal and pathological patterns for both of the above periods are described. The ''dimness'' of the arial tracheogram is emphasized as a usefull and early sign of mediastinal recurrence

  19. 多种病理因素对血管内皮细胞增殖与凋亡的影响及VEGF的干预作用%Inhibitory Effect of Vascular Endothelial Growth Factor on Proliferation and Apoptosis of Vascular Endothelial Cells Induced by Pathological Factors

    Institute of Scientific and Technical Information of China (English)

    刘佳妮; 程燕子; 廖德荣; 曾艳; 叶珊; 刘启功

    2009-01-01

    Objective To evaluate the mechanisms of vascular endothelial growth factor( VEGF)on prevention of restenosis and stent thrombosis after percutaneous coronary intervention (PCI) by observing the effect of VEGF on the proliferation and apoptosis of vascular endothelial cells(VEC)induced by hypoxia,H_2O_2 ,OX-LDL and TNF-α. Methods VEC were divided into control group,hypoxia-treated group, hypoxia + VEGF-treated group, H_2O_2-treated group, H_2O_2 + VEGF-treated group, OX-LDL-treated group,OX-LDL+VEGF-treated group, TNF-α-treated group,and TNF-α+VEGF-treated group. The absorbance (A)value of VEC was examined by WST-1 method,the apoptosis of VEC measured by in situ terminal deoxynucleotidyl trans-ferase(TdT)-mediated deoxyuridine triphosphate(dUTP)-biotin nick end-labeling(TUNEL)and flow cytometry(FCM) ,and the expression of Bcl-2 mRNA and Apo-1/Fas mRNA detected by reverse transcription polymerase chain reaction (RT-PCR). Results As compared with control group and VEGF-treated group, the apoptosis cells and the expression of Apo-1/Fas mRNA were significantly increased in hypoxia-, H_2O_2,OX-LDL- and TNF-α-treated groups, but the A value of VEC and the expression of Bcl-2 mRNA were markedly decreased. Conclusion VEGF could inhibit the proliferation and apoptosis of VEC induced by hypoxia,H_2O_2 ,OX-LDL and TNF-α, which might be correlated with up-regulation of Bcl-2 mRNA expression and down-regulation of the Apo-1/Fas mRNA expression.%目的 研究缺氧、H_2O_2、氧化型低密度脂蛋白(OX-LDL)和肿瘤坏死因子-α(TNF-α)对血管内皮细胞(VEC)增殖、凋亡和凋亡相关基因表达的影响及血管内皮生长因子(VEGF)的干预作用,探讨VEGF预防经皮冠状动脉介入治疗(PCI)后再狭窄和支架内血栓形成的机制.方法 将VEC分成对照组、缺氧处理组、缺氧+VEGF处理组、H_2O_2处理组、H_2O_2+VEGF处理组、OX-LDL处理组、OX-LDL+VEGF处理组、TNF-α处理组和TNF-α+VEGF处理组.利用四氮唑盐比色

  20. [Apoptosis and pathological process].

    Science.gov (United States)

    Rami, Mukhammed Salim Iusef

    2007-01-01

    Apoptosis (programmed cell death) occurs normally for maitenance of tissue homeostasis and play an important role in morphogenesis, embriogenesis and tissue growth. On the other hand, apoptosis may be involved in different pathological processes such as malignancy, infectious diseases and autoimmune disorders. Apoptosis is regulated by various mediators. Caspases, death receptors, mitochondria, Bcl-2 protoncogenes and tumor supressor genes are considered to be the most important of them. Advance in apoptosis regulation research suggests enormouse facilities for therapy of wide range of human illnesses.

  1. Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli.

    Science.gov (United States)

    Rodriguez, Jose A; Orbe, Josune; Martinez de Lizarrondo, Sara; Calvayrac, Olivier; Rodriguez, Cristina; Martinez-Gonzalez, Jose; Paramo, Jose A

    2008-01-01

    Atherosclerosis is the common pathophysiological substrate of ischemic vascular diseases and their thrombotic complications. The unbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) has been hypothesized to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Different MMPs have been assigned relevant roles in the pathology of vascular diseases and MMP-10 (stromelysin-2) has been involved in vascular development and atherogenesis. This article examines the pathophysiological role of MMPs, particularly MMP-10, in the onset and progression of vascular diseases and their regulation by pro-inflammatory stimuli. MMP-10 over-expression has been shown to compromise vascular integrity and it has been associated with aortic aneurysms. MMP-10 is induced by C-reactive protein in endothelial cells, and it is over-expressed in atherosclerotic lesions. Additionally, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and the presence of atherosclerotic plaques. We have cloned the promoter region of the MMP-10 gene and studied the effect of inflammatory stimuli on MMP-10 transcriptional regulation, providing evidences further supporting the involvement of MMP-10 in the pathophysiology of atherothrombosis.

  2. Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.

    Science.gov (United States)

    Barker, Rachel; Ashby, Emma L; Wellington, Dannielle; Barrow, Vivienne M; Palmer, Jennifer C; Kehoe, Patrick G; Esiri, Margaret M; Love, Seth

    2014-05-01

    of reduced ratio of myelin-associated glycoprotein to proteolipid protein 1 are likely to be protective physiological responses to reduced white matter perfusion. Further analysis of the Bristol cohort showed that endothelin 1 was reduced in the white matter in Alzheimer's disease (P < 0.05) compared with control subjects, but not in vascular dementia, in which endothelin 1 tended to be elevated, perhaps reflecting abnormal regulation of white matter perfusion in vascular dementia. Our findings demonstrate the potential of post-mortem measurement of myelin proteins and mediators of vascular function, to assess physiological and pathological processes involved in the regulation of cerebral perfusion in Alzheimer's disease and vascular dementia.

  3. Microglial pathology.

    Science.gov (United States)

    Streit, Wolfgang J; Xue, Qing-Shan; Tischer, Jasmin; Bechmann, Ingo

    2014-09-26

    This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer's disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial pathology and its significance during aging and in the pathogenesis of Alzheimer dementia (AD). The identification of dystrophic (senescent) microglia has created an ostensible conflict with prior work claiming a role for activated microglia and neuroinflammation during normal aging and in AD, and this has raised a basic question: does the brain's immune system become hyperactive (inflamed) or does it become weakened (senescent) in elderly and demented people, and what is the impact on neuronal function and cognition? Here we strive to reconcile these seemingly contradictory notions by arguing that both low-grade neuroinflammation and microglial senescence are the result of aging-associated free radical injury. Both processes are damaging for microglia as they synergistically exhaust this essential cell population to the point where the brain's immune system is effete and unable to support neuronal function.

  4. EVALUATION OF PROGNOSTIC SIGNIFICANCE FOR BIOCHEMICAL MARKERS OF OXIDATIVE STRESS, ENDOGENOUS INTOXICATION AND VASCULAR REGULATION IN THE DEVELOPMENT OF UNFAVORABLE OUTCOMES IN PATIENTS WITH SEPSIS

    Directory of Open Access Journals (Sweden)

    E. V. Klychnikova

    2016-01-01

    Full Text Available Background. Due to the significant infectious complications mortality, the search for prognostic biochemical markers of sepsis development in critically ill patients is relevant.Material and methods. The study involved 57 patients; in 40 cases sepsis developed. The control group included 17 patients where sepsis did not develop. The study was performed on day 1–2, 5–7 and 10–12 after admission. The intensity of oxidative stress was assessed by the level of malondialdehyde (MDA and total antioxidant activity of blood serum (TAA. The endogenous intoxication was assessed by the concentration of medium molecular weight peptides (MMWPs, total and effective albumin concentration (TAC, EAC in serum. The disturbance of endogenous vascular regulation was assessed by the level of stable metabolites of nitric oxide (NOx in serum and the concentration of angiotensin converting enzyme (ACE.Results. It has been found that MDA may be a prognostic index of poor outcome on day 5–7 after admission (relative risk (RR=1.141, confidence interval (CI 95% (1.033; 1.259, р=0.09; NOx level may be a predictor of a poor outcome on day 1–2 (RR=1.026, CI 95% (0.999; 1.055, р=0.064, as well as on day 10–12 (RR=1.012, CI 95% (1.000; 1.023, р=0.098 together with ACE concentration (RR=1.034, CI 95% (1.007; 1.062, р=0.015; MMWP254 level (RR=11.195, CI 95% (1.571; 79.771, р=0.016 and MMWP280 level (RR=17.370, CI 95% (1.568; 192.455, р=0.02 are significant predictors of a poor outcome on day 1–2 and 5–7 as well (MMWP254 — RR=4626.791, CI 95% (7.903; 27808.629, р=0.009 and MMWP280 — RR=1331.590, CI 95% (5.006; 354179.342, р=0.012.Conclusion. We identified prognostically significant signs of unfavorable outcomes of septic process: decrease in NOx; growth of ACE concentration; increase in MDA and decrease in TAA; increase in MMWPs; decrease in TAC and EAC.

  5. Zinc regulates Nox1 expression through a NF-κB and mitochondrial ROS dependent mechanism to induce senescence of vascular smooth muscle cells.

    Science.gov (United States)

    Salazar, G; Huang, J; Feresin, R G; Zhao, Y; Griendling, K K

    2017-07-01

    The role of oxidative stress and inflammation in the development and progression of cardiovascular diseases (CVD) is well established. Increases in oxidative stress can further exacerbate the inflammatory response and lead to cellular senescence. We previously reported that angiotensin II (Ang II) and zinc increase reactive oxygen species (ROS) and cause senescence of vascular smooth muscle cells (VSMCs) and that senescence induced by Ang II is a zinc-dependent process. Zinc stimulated NADPH oxidase (Nox) activity; however, the role of Nox isoforms in zinc effects was not determined. Here, we show that downregulation of Nox1, but not Nox4, by siRNA prevented both Ang II- and zinc-induced senescence in VSMCs. On the other hand, overexpression of Nox1 induced senescence, which was associated with reduced proliferation, reduced expression of telomerase and increased DNA damage. Zinc increased Nox1 protein expression, which was inhibited by chelation of zinc with TPEN and by overexpression of the zinc exporters ZnT3 and ZnT10. These transporters work to reduce cytosolic zinc, suggesting that increased cytosolic zinc mediates Nox1 upregulation. Other metals including copper, iron, cobalt and manganese failed to upregulate Nox1, suggesting that this pathway is zinc specific. Nox1 upregulation was inhibited by actinomycin D (ACD), an inhibitor of transcription, by inhibition of NF-κB, a known Nox1 transcriptional regulator and by N-acetyl cysteine (NAC) and MitoTEMPO, suggesting that NF-κB and mitochondrial ROS mediate zinc effects. Supporting this idea, we found that zinc increased NF-κB activation in the cytosol, stimulated the translocation of the p65 subunit to the nucleus, and that zinc accumulated in mitochondria increasing mitochondrial ROS, measured using MitoSox. Further, zinc-induced senescence was reduced by inhibition of NF-κB or reduction of mitochondrial ROS with MitoTEMPO. NF-κB activity was also reduced by MitoTEMPO, suggesting that mitochondrial ROS

  6. Vascular ultrasound.

    Science.gov (United States)

    Pilcher, D B; Ricci, M A

    1998-04-01

    Surgeon-interpreted diagnostic ultrasound has become the preferred screening test and often the definitive test for the diagnosis of arterial stenosis, aneurysm, and venous thrombosis. As a modality for surveillance, its noninvasive quality makes it particularly appealing as the test of choice to screen patients for abdominal aortic aneurysms or to perform follow-up examinations on those patients with a carotid endartectomy or in situ bypass grafts. The increasing reliance on intraoperative duplex imaging of vascular procedures demands that the surgeon learn the skills to perform the studies without a technologist or radiologist to interpret the examination.

  7. On the pathologically altered pulmonary pattern

    International Nuclear Information System (INIS)

    Ginzburg, M.A.; Kinoshenko, Yu.T.

    1982-01-01

    The notions ''normal'' and ''pathologically altered pulmonary pattern'' are specified. A grouping of lung pattern alterations based on morphopathogenetic features is provided: blood and lymphatic vascular alterations, changes in the bronchi, lung stroma, and combined alterations. Radiologic appearance of the altered pulmonary pattern is classified in keeping with the basic principles of an X-ray shade examination. The terms, such as ''enriching'', ''strengthening'', ''deformation'', etc., used for describing the pathologically altered pulmonary pattern are defined

  8. [Pathologic gambling].

    Science.gov (United States)

    Nespor, K

    1996-01-31

    The author presents a review on pathological gambling. Similarly as in other addictive diseases, early therapeutic intervention is important. The latter may include: 1: Evaluation of the problem 2. Recommendation that the subject should avoid places where the gambling is pursued. He should not have larger financial sums on him. 3. Recommendations pertaining to lifestyle and prevention of excessive stress. 4. Handling of printed material (the author mentions the text issued to his patients). In the paper therapeutic procedures are described, incl. the author's experience such as the foundation of the group of Gamblers anonymous. Prevention is also considered. It is important that gambling should be less readily available and the demand for it should be smaller.

  9. Contemporary vascular smartphone medical applications.

    Science.gov (United States)

    Carter, Thomas; O'Neill, Stephen; Johns, Neil; Brady, Richard R W

    2013-08-01

    Use of smartphones and medical mHealth applications (apps) within the clinical environment provides a potential means for delivering elements of vascular care. This article reviews the contemporary availability of apps specifically themed to major vascular diseases and the opportunities and concerns regarding their integration into practice. Smartphone apps relating to major vascular diseases were identified from the app stores for the 6 most popular smartphone platforms, including iPhone, Android, Blackberry, Nokia, Windows, and Samsung. Search terms included peripheral artery (arterial) disease, varicose veins, aortic aneurysm, carotid artery disease, amputation, ulcers, hyperhydrosis, thoracic outlet syndrome, vascular malformation, and lymphatic disorders. Forty-nine vascular-themed apps were identified. Sixteen (33%) were free of charge. Fifteen apps (31%) had customer satisfaction ratings, but only 3 (6%) had greater than 100. Only 13 apps (27%) had documented medical professional involvement in their design or content. The integration of apps into the delivery of care has the potential to benefit vascular health care workers and patients. However, high-quality apps designed by clinicians with vascular expertise are currently lacking and represent an area of concern in the mHealth market. Improvement in the quality and reliability of these apps will require the development of robust regulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. SEX DIFFERENCES OF VLF100 AND VLF50 SPECTRUM OF HEART RATE VARIABILITY IN HEALTHY INDIVIDUALS OF YOUNG AGE AND OLDER SUBJECTS WITH VASCULAR PATHOLOGY IN TERMS OF SEVEN-TEST, HYPERVENTILATION AND ORTHOSTASIS

    Directory of Open Access Journals (Sweden)

    Арнольд Наумович Флейшман

    2017-10-01

    Conclusion. The results of sex differences of the new VLF100 and VLF50 indicators and their interconnection with LF and HF were essential to the study of autonomic provision in the body, characterizing central mechanisms of regulation.

  11. Ionizing radiation activates vascular endothelial growth factor-A transcription in human umbilical vein endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyounji; Kim, Kwang Seok; Jeong, Jae Hoon; Lim, Young Bin [Radiation Cancer Biology Team, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2016-12-15

    Vascular endothelial growth factor (VEGF) is an essential paracrine factor for developmental and pathological angiogenesis. VEGF also exerts its effects in an autocrine manner in VEGF-producing cells. For instance, autocrine VEGF signaling occurs in tumor cells and contributes to key aspects of tumorigenesis, such as in the function of cancer stem cells and tumor initiation, which are independent of angiogenesis. In addition to tumors cells, non-transformed cells also express VEGF. For example, a VEGF dependent intracellular autocrine mechanism is crucial for the survival of hematopoietic stem cells and hematopoiesis. Stereotactic body radiation therapy (SBRT) is a novel treatment modality for early primary cancer and oligometastatic disease. SBRT delivers high-dose hypofractionated radiation, such as 20-60 Gy, to tumors in a single fraction or 2-5 fractions. As VEGF is a critical regulator of functional integrity and viability of vascular endothelial cells, we examined whether high-dose irradiation alters VEGF signaling by measuring the expression levels of VEGFA transcript. It is generally believed that endothelial cells do not produce VEGF in response to radiation. In present study, however, we provide the first demonstration of transcriptional regulation of VEGFA in human vascular endothelial cells by IR treatment. Irradiation with doses higher than 10 Gy in a single exposure triggers up-regulation of VEGFA transcription within 2 hours in HUVECs, whereas irradiation with 10 Gy does not alter VEGFA levels. Our data have shown that high-dose irradiation triggers immediate transactivation of VEGFA in human vascular endothelial cells.

  12. Arabidopsis wat1 (walls are thin1)-mediated resistance to the bacterial vascular pathogen, Ralstonia solanacearum, is accompanied by cross-regulation of salicylic acid and tryptophan metabolism

    NARCIS (Netherlands)

    Denancé, N.; Ranocha, P.; Oria, N.; Barlet, X.; Rivière, M.P.; Yadeta, K.A.; Hoffmann, L.; Perreau, F.; Clément, G.; Maia-Grondard, A.; Berg, van den G.C.M.; Savelli, B.; Fournier, S.; Aubert, Y.; Pelletier, S.; Thomma, B.P.H.J.; Molina, A.; Jouanin, L.; Marco, Y.; Goffner, D.

    2013-01-01

    Inactivation of Arabidopsis WAT1 (Walls Are Thin1), a gene required for secondary cell-wall deposition, conferred broad-spectrum resistance to vascular pathogens, including the bacteria Ralstonia solanacearum and Xanthomonas campestris pv. campestris, and the fungi Verticillium dahliae and

  13. MiR-29-mediated elastin down-regulation contributes to inorganic phosphorus-induced osteoblastic differentiation in vascular smooth muscle cells.

    Science.gov (United States)

    Sudo, Ryo; Sato, Fumiaki; Azechi, Takuya; Wachi, Hiroshi

    2015-12-01

    Vascular calcification increases the risk of cardiovascular mortality. We previously reported that expression of elastin decreases with progression of inorganic phosphorus (Pi)-induced vascular smooth muscle cell (VSMC) calcification. However, the regulatory mechanisms of elastin mRNA expression during vascular calcification remain unclear. MicroRNA-29 family members (miR-29a, b and c) are reported to mediate elastin mRNA expression. Therefore, we aimed to determine the effect of miR-29 on elastin expression and Pi-induced vascular calcification. Calcification of human VSMCs was induced by Pi and evaluated measuring calcium deposition. Pi stimulation promoted Ca deposition and suppressed elastin expression in VSMCs. Knockdown of elastin expression by shRNA also promoted Pi-induced VSMC calcification. Elastin pre-mRNA measurements indicated that Pi stimulation suppressed elastin expression without changing transcriptional activity. Conversely, Pi stimulation increased miR-29a and miR-29b expression. Inhibition of miR-29 recovered elastin expression and suppressed calcification in Pi-treated VSMCs. Furthermore, over-expression of miR-29b promoted Pi-induced VSMC calcification. RT-qPCR analysis showed knockdown of elastin expression in VSMCs induced expression of osteoblast-related genes, similar to Pi stimulation, and recovery of elastin expression by miR-29 inhibition reduced their expression. Our study shows that miR-29-mediated suppression of elastin expression in VSMCs plays a pivotal role in osteoblastic differentiation leading to vascular calcification. © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  14. Macrophage Metalloelastase (MMP-12) Deficiency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy

    Science.gov (United States)

    Li, Jingming; Wang, Joshua J.; Peng, Qisheng; Chen, Chen; Humphrey, Mary Beth; Heinecke, Jay; Zhang, Sarah X.

    2012-01-01

    Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis. PMID:23285156

  15. Vascular remodeling and mineralocorticoids.

    Science.gov (United States)

    Weber, K T; Sun, Y; Campbell, S E; Slight, S H; Ganjam, V K

    1995-01-01

    Circulating mineralocorticoid hormones are so named because of their important homeostatic properties that regulate salt and water balance via their action on epithelial cells. A broader range of functions in nonclassic target cellular sites has been proposed for these steroids and includes their contribution to wound healing following injury. A chronic, inappropriate (relative to intravascular volume and dietary sodium intake) elevation of these circulating hormones evokes a wound healing response in the absence of tissue injury--a wound healing response gone awry. The adverse remodeling of vascularized tissues seen in association with chronic mineralocorticoid excess is the focus of this review.

  16. Pathology annual. Part 1/Volume 23

    International Nuclear Information System (INIS)

    Rosen, P.P.; Fechner, R.E.

    1988-01-01

    This book contains 11 papers. Some of the titles are: Evaluation of Breast Biopsy Specimens in Patients Considered for Treatment by Conservative Surgery and Radiation Therapy for Early Breast Cancer; Magnetic Resonance Imaging of the Human Female Breast: Current Status and Pathologic Correlations; Ovarian Sex Cord-Stromal Tumors: Problems in Differential Diagnosis; and Vascular Lesions Following Radiation

  17. Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses.

    Science.gov (United States)

    Gronert, K; Martinsson-Niskanen, T; Ravasi, S; Chiang, N; Serhan, C N

    2001-01-01

    Aspirin-triggered lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D(4) (LTD(4)) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD(4) receptor (CysLT(1)) is induced in human vascular endothelia by interleukin-1beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [(3)H]-LTD(4) and a novel labeled mimetic of ATL ([(3)H]-ATLa) that was displaced with LTD(4) and ATLa ( approximately IC(50) 0.2 to 0.9 nmol/L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [(3)H]-ATLa (IC(50) approximately 8.3 nmol/L). In contrast, LTD(4) was an ineffective competitive ligand for recombinant ALX receptor with [(3)H]-ATLa, and ATLa did not compete for [(3)H]-LTB(4) binding with recombinant LTB(4) receptor. Endogenous murine CysLT(1) receptors also gave specific [(3)H]-ATLa binding that was displaced with essentially equal affinity by LTD(4) or ATLa. Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 microg/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 microg/kg). These results indicate that ATL and LTD(4) bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

  18. Vascular endothelial growth factors and angiogenesis in eye disease

    NARCIS (Netherlands)

    Witmer, A. N.; Vrensen, G. F. J. M.; van Noorden, C. J. F.; Schlingemann, R. O.

    2003-01-01

    The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights

  19. Vascular endothelial growth factor and basic fibroblast growth factor expression positively correlates with angiogenesis and peritumoural brain oedema in astrocytoma

    International Nuclear Information System (INIS)

    Jang, F.F.; Wei, W.

    2008-01-01

    Astrocytoma is the most malignant intracranial neoplasm and is characterized by high neovascularization and peritumoural brain oedema. Angiogenesis is a complicated process in oncogenesis regulated by the balance between angiogenic and antiangiogenic factors. The expression of two angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor were investigated using immunohistochemistry for astrocytoma from 82 patients and 11 normal human tissues. The expression of vascular endothelial growth factor and basic fibroblast growth factor positively correlate with the pathological grade of astrocytoma, microvessel density numbers and brain oedema, which may be responsible for the increased tumour neovascularization and peritumoural brain oedema. The results support the idea that inhibiting vascular endothelial growth factor and basic fibroblast growth factor are useful for the treatment of human astrocytoma and to improve patient's clinical outcomes and prognosis. (author)

  20. IL-4/5 signalling plays an important role during Litomosoides sigmodontis infection, influencing both immune system regulation and tissue pathology in the thoracic cavity.

    Science.gov (United States)

    Ritter, Manuel; Tamadaho, Ruth S; Feid, Judith; Vogel, Wenzel; Wiszniewsky, Katharina; Perner, Sven; Hoerauf, Achim; Layland, Laura E

    2017-12-01

    Approximately 100 million people suffer from filarial diseases including lymphatic filariasis (elephantiasis), onchocerciasis (river blindness) and loiasis. These diseases are amongst the most devastating of the neglected tropical diseases in terms of social and economic impact. Moreover, many infection-induced immune mechanisms in the host, their relationship to disease-related symptoms and the development of pathology within the site of infection remain unclear. To improve on current drug therapies or vaccines, further studies are necessary to decipher the mechanisms behind filaria-driven immune responses and pathology development, and thus the rodent model of Litomosoides sigmodontis can be used to unravel host-filaria interactions. Interestingly, BALB/c mice develop a patent state (release of microfilariae, the transmission life-stage, into the periphery) when exposed to L. sigmodontis. Thus, using this model, we determined levels of host inflammation and pathology development during a L. sigmodontis infection in vivo for the first known time. Our study reveals that after 30days p.i., inflammation and pathology began to develop in infected wild type BALB/c mice between the lung and diaphragm, close to the site of infection - the thoracic cavity. Interestingly, infected IL-4Rα/IL-5 -/- BALB/c mice had accentuated inflammation of the pleural lung and pleural diaphragm, and higher parasite burdens. Corresponding to the pleural inflammation, levels of IP-10, MIP-1α, MIP-1β, MIP-2 and RANTES were significantly elevated in the thoracic cavity fluid of infected IL-4Rα/IL-5 -/- mice compared with wild type controls. Moreover, upon L. sigmodontis antigen stimulation, IFN-γ and IL-17A secretions by cells isolated from draining lymph nodes of IL-4Rα/IL-5 -/- mice were significantly elevated, whereas secretion of IL-5, IL-13 and IL-10 was reduced. Elevated filaria-specific IFN-γ secretion was also observed in spleen-derived CD4 + T cell co-cultures from IL-4Rα/IL-5

  1. Essential Roles of Raf/Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway, YY1, and Ca2+ Influx in Growth Arrest of Human Vascular Smooth Muscle Cells by Bilirubin*

    Science.gov (United States)

    Stoeckius, Marlon; Erat, Anna; Fujikawa, Tatsuya; Hiromura, Makoto; Koulova, Anna; Otterbein, Leo; Bianchi, Cesario; Tobiasch, Edda; Dagon, Yossi; Sellke, Frank W.; Usheva, Anny

    2012-01-01

    The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK pathway and the cellular Raf and cyclin D1 content that results in retinoblastoma protein hypophosphorylation on amino acids S608 and S780. These events impede the release of YY1 to the nuclei and its availability to regulate the expression of genes and to support cellular proliferation. Moreover, altered calcium influx and calpain II protease activation leads to proteolytical degradation of transcription factor YY1. We conclude that in the serum-stimulated human vascular smooth muscle primary cell cultures, bilirubin favors growth arrest, and we propose that this activity is regulated by its interaction with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. We propose that these activities together culminate in diminished 5 S and 45 S ribosomal RNA synthesis and cell growth arrest. The observations provide important mechanistic insight into the molecular mechanisms underlying the transition of human vascular smooth muscle cells from proliferative to contractile phenotype and the role of bilirubin in this transition. PMID:22262839

  2. Proatherogenic pathways leading to vascular calcification

    International Nuclear Information System (INIS)

    Mazzini, Michael J.; Schulze, P. Christian

    2006-01-01

    Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. The pathogenesis of atherosclerosis involves local vascular injury, inflammation and oxidative stress as well as vascular calcification. Vascular calcification has long been regarded as a degenerative process leading to mineral deposition in the vascular wall characteristic for late stages of atherosclerosis. However, recent studies identified vascular calcification in early stages of atherosclerosis and its occurrence has been linked to clinical events in patients with cardiovascular disease. Its degree correlates with local vascular inflammation and with the overall impact and the progression of atherosclerosis. Over the last decade, diverse and highly regulated molecular signaling cascades controlling vascular calcification have been described. Local and circulating molecules such as osteopontin, osteoprogerin, leptin and matrix Gla protein were identified as critical regulators of vascular calcification. We here review the current knowledge on molecular pathways of vascular calcification and their relevance for the progression of cardiovascular disease

  3. Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series.

    Science.gov (United States)

    Atchison, Elizabeth A; Garrity, James A; Castillo, Francisco; Engman, Steven J; Couch, Steven M; Salomão, Diva R

    2016-01-01

    Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit. Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic. A total of 52 patients who underwent removal of vascular orbital lesions. The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3). The existence and pattern of staining with VEGF and its subtypes on these lesions. There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse. Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  4. mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.

    Science.gov (United States)

    Jahrling, Jordan B; Lin, Ai-Ling; DeRosa, Nicholas; Hussong, Stacy A; Van Skike, Candice E; Girotti, Milena; Javors, Martin; Zhao, Qingwei; Maslin, Leigh Ann; Asmis, Reto; Galvan, Veronica

    2018-01-01

    We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR -/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

  5. IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis.

    Science.gov (United States)

    Tarantini, Stefano; Giles, Cory B; Wren, Jonathan D; Ashpole, Nicole M; Valcarcel-Ares, M Noa; Wei, Jeanne Y; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

    2016-08-01

    Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1 f/f mice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the

  6. Curriculum Guidelines for Pathology and Oral Pathology.

    Science.gov (United States)

    Journal of Dental Education, 1985

    1985-01-01

    Guidelines for dental school pathology courses describe the interrelationships of general, systemic, and oral pathology; primary educational goals; prerequisites; a core curriculum outline and behavioral objectives for each type of pathology. Notes on sequencing, faculty, facilities, and occupational hazards are included. (MSE)

  7. Normal and pathological breast, the histological basis

    Energy Technology Data Exchange (ETDEWEB)

    Guinebretiere, J.M. [Department of Pathology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France)]. E-mail: jm.guinebretiere@stcloud-huguenin.org; Menet, E. [Department of Pathology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France); Tardivon, A. [Department of Radiology, Institut Curie, 26 rue d' Ulm, 75248 Paris Cedex 5 (France); Cherel, P. [Department of Radiology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France); Vanel, D. [Department of Diagnostic Radiology, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif (France)

    2005-04-01

    Breast tissue is heterogeneous, associating connective and glandular structures, which grow and change cyclically under hormonal regulation. Hormones are also thought to be the main determinant of the major benign and malignant pathologies encountered in the breast. Benign lesions are more frequent and fibrocystic changes are by far the most common among them. They usually associate different entities (adenosis, fibrosis, cysts and hyperplasia) but vary in intensity and extension. Thus, their clinical and radiographic presentation is extremely different from one patient to another. Adenofibroma is the most frequent tumour. It also undergoes modifications according to hormonal conditions. About 90% of malignant tumours are primary carcinoma. The incidence of intra-ductal carcinoma has risen dramatically since the development of screening because of its ability to induce calcification. Two mechanisms could be involved in the formation of calcification: one active (tumour cell secretion of vesicles), the other passive (necrotic cell fragments are released). Invasive carcinoma comprises numerous histological types. Stromal reactions essentially determines their shape: a fibrous reaction commonly found in ductal carcinoma creates a stellate lesion while other stroma, inflammatory (medullary carcinoma), vascular (papillary carcinoma) or mucinous determine nodular lesions whose borders push the surrounding tissue. The histological features which give rise to the radiographic pattern will be emphasised.

  8. Vascular mechanotransduction data in a rodent model of diabetes: Pressure-induced regulation of SHP2 and associated signaling in the rat inferior vena cava

    Directory of Open Access Journals (Sweden)

    Kevin M. Rice

    2017-12-01

    Full Text Available The effect of diabetes on vascular mechano-transductive response is of great concern. Given the higher rate of vein graft failures associated with diabetes, understanding the multiple cellular and molecular events associated with vascular remodeling is of vital importance. This article represents data related to a study published in Cardiovascular Diabetology [1] (Rice et al., 2006 and Open Journal of Endocrine and Metabolic Diseases [2] (Rice et al., 2015 evaluating the effect of pressurization on rat inferior venae cavae (IVC. Provided within this articles is information related to the method and processing of raw data related to our prior publish work and Data in Brief articles [3,4] (Rice et al., 2017, as well as the evaluation of alternation in SHP-2 signaling and associated proteins in response to mechanical force. IVC from lean and obese animals were exposed to a 30 min perfusion of 120 mm Hg pressure and evaluated for changes in expression of SHP2, BCL-3, BCL-XL, HSP 27, HSP 70, and PI3K p85, along with the phosphorylation of SHP-2 (Tyr 542.

  9. Diagnostics of vascular diseases as a cause for acute abdomen

    International Nuclear Information System (INIS)

    Juchems, M.S.; Aschoff, A.J.

    2010-01-01

    Vascular pathologies are rare causes of an acute abdomen. If the cause is a vascular disease a rapid diagnosis is desired as vascular pathologies are associated with high mortality. A differentiation must be made between arterial and venous diseases. An occlusion of the superior mesenteric artery is the most common reason for acute mesenteric ischemia but intra-abdominal arterial bleeding is also of great importance. Venous pathologies include thrombotic occlusion of the portal vein, the mesenteric vein and the vena cava. Multi-detector computed tomography (MDCT) is predestined for the diagnostics of vascular diseases of the abdomen. Using multiphasic contrast protocols enables reliable imaging of the arterial and venous vessel tree and detection of disorders with high sensitivity and specificity. Although conventional angiography has been almost completely replaced by MDCT as a diagnostic tool, it is still of high importance for minimally invasive interventions, for example in the management of gastrointestinal bleeding. (orig.) [de

  10. [The regulation of microecological disorders of the intestines in newborn infants with perinatal pathology using the new probiotic bifidumbacterin-forte].

    Science.gov (United States)

    Iakushenko, M N; Tkhagapsoeva, Zh M; Bondarenko, V M

    1997-01-01

    The study was made on 93 newborn infants with perinatal pathology, among them infants with the perinatal lesion of the central nervous system (52), hemolytic disease of newborns (19) and conjugation jaundice (12). All newborn infants were examined for the presence of intestinal microflora in its dynamics and for the state microbiocenosis, evaluated by the rapid method based on the determination of the caseinolytic activity of fecal supernatants after the correction of normal flora with bifidumbacterin in 55 infants and with bifidumbacterin-forte in 38 infants. The comparative study of these two preparations revealed that the use of probiotics containing Bifidobacterium bifidum was mainly substitutional, promoting the colonization of the intestine by lactobacteria, which later determined the suppression opportunistic microflora. The effectiveness of bifidumbacterin-forte containing live B. bifidum, immobilized on sorbent, proved to be most pronounced.

  11. Bioprinting for vascular and vascularized tissue biofabrication.

    Science.gov (United States)

    Datta, Pallab; Ayan, Bugra; Ozbolat, Ibrahim T

    2017-03-15

    Bioprinting is a promising technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision. Bioprinting enables the deposition of various biologics including growth factors, cells, genes, neo-tissues and extra-cellular matrix-like hydrogels. Benefits of bioprinting have started to make a mark in the fields of tissue engineering, regenerative medicine and pharmaceutics. Specifically, in the field of tissue engineering, the creation of vascularized tissue constructs has remained a principal challenge till date. However, given the myriad advantages over other biofabrication methods, it becomes organic to expect that bioprinting can provide a viable solution for the vascularization problem, and facilitate the clinical translation of tissue engineered constructs. This article provides a comprehensive account of bioprinting of vascular and vascularized tissue constructs. The review is structured as introducing the scope of bioprinting in tissue engineering applications, key vascular anatomical features and then a thorough coverage of 3D bioprinting using extrusion-, droplet- and laser-based bioprinting for fabrication of vascular tissue constructs. The review then provides the reader with the use of bioprinting for obtaining thick vascularized tissues using sacrificial bioink materials. Current challenges are discussed, a comparative evaluation of different bioprinting modalities is presented and future prospects are provided to the reader. Biofabrication of living tissues and organs at the clinically-relevant volumes vitally depends on the integration of vascular network. Despite the great progress in traditional biofabrication approaches, building perfusable hierarchical vascular network is a major challenge. Bioprinting is an emerging technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision

  12. Molecular pathology of bone tumours: diagnostic implications.

    Science.gov (United States)

    Puls, Florian; Niblett, Angela J; Mangham, D Chas

    2014-03-01

    Alongside histomorphology and immunohistochemistry, molecular pathology is now established as one of the cornerstones in the tissue diagnosis of bone tumours. We describe the principal molecular pathological techniques employed, and each of the bone tumour entities where their identified characteristic molecular pathological changes can be detected to support and confirm the suspected histological diagnosis. Tumours discussed include fibrous dysplasia, classical and subtype osteosarcomas, central and surface cartilaginous tumours, Ewing's sarcoma, vascular tumours, aneurysmal bone cyst, chordoma, myoepithelioma, and angiomatoid fibrous histiocytoma. This is a rapidly evolving field with discoveries occurring every few months, and some of the newer entities (the Ewing's-like sarcomas), which are principally identified by their molecular pathology characteristics, are discussed. © 2013 John Wiley & Sons Ltd.

  13. Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Wenmeng Wang

    Full Text Available High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC and human aortic endothelial cells (HAEC down-regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP-induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down-regulation. The over-expression of nucleolin by gene transfer partly reversed ADP-induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down-regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin.

  14. The Danish Pathology Register

    DEFF Research Database (Denmark)

    Bjerregaard, Beth; Larsen, Ole B

    2011-01-01

    The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established.......The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established....

  15. Vascular neurocognitive disorders and the vascular risk factors

    Directory of Open Access Journals (Sweden)

    Carmen V. Albu

    2018-04-01

    Full Text Available Dementias are clinical neurodegenerative diseases characterized by permanent and progressive transformation of cognitive functions such as memory, learning capacity, attention, thinking, language, passing judgments, calculation or orientation. Dementias represent a relatively frequent pathology, encountered at about 10% of the population of 65-year olds and 20% of the population of 80-year olds. This review presents the main etiological forms of dementia, which include Alzheimer form of dementia, vascular dementia, dementia associated with alpha-synucleionopathies, and mixed forms. Regarding vascular dementia, the risk factors are similar to those for an ischemic or hemorrhagic cerebrovascular accident: arterial hypertension, diabetes mellitus, dyslipidemia, smoking, obesity, age, alcohol consumption, cerebral atherosclerosis/ arteriosclerosis. Several studies show that efficient management of the vascular risk factors can prevent the expression and/ or progression of dementia. Thus, lifestyle changes such as stress reduction, regular physical exercise, decreasing dietary fat, multivitamin supplementation, adequate control of blood pressure and serum cholesterol, and social integration and mental stimulation in the elderly population are important factors in preventing or limiting the symptoms of dementia, a disease with significant individual, social, and economic implications.

  16. Abl family kinases regulate endothelial barrier function in vitro and in mice.

    Directory of Open Access Journals (Sweden)

    Elizabeth M Chislock

    Full Text Available The maintenance of endothelial barrier function is essential for normal physiology, and increased vascular permeability is a feature of a wide variety of pathological conditions, leading to complications including edema and tissue damage. Use of the pharmacological inhibitor imatinib, which targets the Abl family of non-receptor tyrosine kinases (Abl and Arg, as well as other tyrosine kinases including the platelet-derived growth factor receptor (PDGFR, Kit, colony stimulating factor 1 receptor (CSF1R, and discoidin domain receptors, has shown protective effects in animal models of inflammation, sepsis, and other pathologies characterized by enhanced vascular permeability. However, the imatinib targets involved in modulation of vascular permeability have not been well-characterized, as imatinib inhibits multiple tyrosine kinases not only in endothelial cells and pericytes but also immune cells important for disorders associated with pathological inflammation and abnormal vascular permeability. In this work we employ endothelial Abl knockout mice to show for the first time a direct role for Abl in the regulation of vascular permeability in vivo. Using both Abl/Arg-specific pharmacological inhibition and endothelial Abl knockout mice, we demonstrate a requirement for Abl kinase activity in the induction of endothelial permeability by vascular endothelial growth factor both in vitro and in vivo. Notably, Abl kinase inhibition also impaired endothelial permeability in response to the inflammatory mediators thrombin and histamine. Mechanistically, we show that loss of Abl kinase activity was accompanied by activation of the barrier-stabilizing GTPases Rac1 and Rap1, as well as inhibition of agonist-induced Ca(2+ mobilization and generation of acto-myosin contractility. In all, these findings suggest that pharmacological targeting of the Abl kinases may be capable of inhibiting endothelial permeability induced by a broad range of agonists and that use

  17. Vascular homeostasis regulators, Edn1 and Agpt2, are upregulated as a protective effect of heat-treated zinc yeast in irradiated murine bone marrow

    International Nuclear Information System (INIS)

    Ueno, Megumi; Imadome, Kaori; Iwakawa, Mayumi; Anzai, Kazunori; Ikota, Nobuo; Imai, Takashi

    2010-01-01

    The purpose of this study was to elucidate the mechanism underlying the in vivo radioprotection activity by Zn-containing, heat-treated Saccharomyces cerevisiae yeast (Zn-yeast). Zn-yeast suspension was administered into C3H/He mice immediately after whole body irradiation (WBI) at 7.5 Gy. Bone marrow was extracted from the mice 6 hours after irradiation and analyzed on a microarray. Expression changes in the candidate responsive genes differentially expressed in treated mice were re-examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The bone marrow was also examined pathologically at 6 h, 3, 7, and 14 days postirradiation. Thirty-six genes, including Edn1 and Agpt2, were identified as candidate responsive genes in irradiated mouse bone marrow treated with Zn-yeast by showing a greater than three-fold change compared with control (no irradiation and no Zn-yeast) mice. The expressions of Cdkn1a, Bax, and Ccng, which are well known as radioresponsive genes, were upregulated in WBI mice and Zn-yeast treated WBI mice. Pathological examination showed the newly formed microvessels lined with endothelial cells, and small round hematopoietic cells around vessels in bone marrow matrix of mice administered with Zn-yeast after WBI, while whole-body irradiated mice developed fatty bone marrow within 2 weeks after irradiation. This study identified a possible mechanism for the postirradiation protection conferred by Zn-yeast. The protective effect of Zn-yeast against WBI is related to maintaining the bone marrow microenvironment, including targeting endothelial cells and cytokine release. (author)

  18. Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication.

    Science.gov (United States)

    Osanai, Makoto

    2017-06-01

    Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  19. Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

    Science.gov (United States)

    Fujii, Hidetaka; Shin-Ya, Masaharu; Takeda, Shigeo; Hashimoto, Yoshihide; Mukai, Sada-atsu; Sawada, Shin-ichi; Adachi, Tetsuya; Akiyoshi, Kazunari; Miki, Tsuneharu; Mazda, Osam

    2014-12-01

    RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  20. RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG

    NARCIS (Netherlands)

    Yuan, Lei; Sacharidou, Anastasia; Stratman, Amber N.; Le Bras, Alexandra; Zwiers, Peter J.; Spokes, Katherine; Bhasin, Manoj; Shih, Shou-ching; Nagy, Janice A.; Molema, Grietje; Aird, William C.; Davis, George E.; Oettgen, Peter

    2011-01-01

    ERG is a member of the ETS transcription factor family that is highly enriched in endothelial cells (ECs). To further define the role of ERG in regulating EC function, we evaluated the effect of ERG knockdown on EC lumen formation in 3D collagen matrices. Blockade of ERG using siRNA completely

  1. Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study.

    Science.gov (United States)

    Brown, Karryn L; Seale, Kirsten B; El Khoury, Louis Y; Posthumus, Michael; Ribbans, William J; Raleigh, Stuart M; Collins, Malcolm; September, Alison V

    2017-08-01

    Several genetic loci have been associated with risk of Achilles tendon pathology (ATP) within South African and Australian populations. The aim of this study was, therefore, to evaluate eight previously implicated genetic variants in an independent British population. A total of 130 asymptomatic controls (CON) and 112 participants clinically diagnosed with ATP comprising 87 individuals with chronic Achilles tendinopathy (TEN) and 25 with Achilles tendon ruptures (RUP) were included. All participants were genotyped for variants within the COL5A1, MIR608, IL-1β, IL-6 and CASP8 genes. Primary findings implicated COL5A1 and CASP8. Three inferred allele combinations constructed from COL5A1 rs12722, rs3196378 and rs71746744 were identified as risk modifiers. The T-C-D combination was associated with increased risk of ATP (P = 0.023) and RUP (P RUP (P = 0.011) and the C-C-D combination was associated with decreased risk of ATP (P = 0.011) and RUP (P = 0.004). The CASP8 rs3834129 DD genotype was associated with decreased risk of TEN (P = 0.020, odds ratio: 0.45, 95% confidence interval: 0.22-0.90) and the CASP8 I-G (rs3834129-rs1045485) inferred allele combination was associated with increased risk of TEN (P = 0.031). This study further highlights the importance of polymorphisms within COL5A1 and CASP8 in the aetiology of ATP.

  2. Vascular function in health, hypertension, and diabetes

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Gliemann, Lasse; Hellsten, Ylva

    2015-01-01

    muscle, which can affect muscle function. Central aspects in the vascular impairments are alterations in the formation of prostacyclin, the bioavailability of NO and an increased formation of vasoconstrictors and reactive oxygen species (ROS). Regular physical activity effectively improves vascular......, the increase in muscle blood flow required for oxygen supply during exercise is achieved through a substantial increase in vasodilators locally formed in the active muscle tissue that overcome the vasoconstrictor signals. Most of the vasodilator signals are mediated via endothelial cells, which lead...... to the formation of vasodilators such as nitric oxide (NO) and prostacyclin. In essential hypertension and type II diabetes, the endothelial function and regulation of vascular tone is impaired with consequent increases in peripheral vascular resistance and inadequate regulation of oxygen supply to the skeletal...

  3. Effect of tamoxifen, methoxyprogesterone acetate and combined treatment on cellular proliferation and apoptosis in SKOV3/DDP cells via the regulation of vascular endothelial growth factor.

    Science.gov (United States)

    Wen, Lv; Hong, Ding; Yanyin, Wu; Mingyue, Zhang; Baohua, Li

    2013-05-01

    The aim of this study was to investigate the effect of tamoxifen (TAM), methoxyprogesterone acetate (MPA) and their combined treatment on cisplatin-resistant ovarian cancer SKOV3/DDP cells, as well as the potential mechanisms. MTT assay was used to investigate the effect of different concentrations (0.01, 0.1, 1, 10 and 100 μM) of TAM, MPA and their combined treatment on the proliferation of cisplatin-resistant ovarian cancer SKOV3/DDP cells. Flow cytometry was employed to analyze the cell cycle and apoptosis rate of SKOV3/DDP cells treated with medium concentration (10 μM) of TAM, MPA and their combined treatment. Change in the protein level of vascular endothelial growth factor (VEGF) in response to drug treatments was measured using Western-blot. The proliferation of SKOV3/DDP cells was inhibited by 1, 10 and 100 μM of TAM or MPA in a dose-dependent manner. Compared to the control group, 10 μM TAM could significantly arrest SKOV3/DDP cells in the G0/G1 stage and induce apoptosis (p < 0.01). However, 10 μM MPA only promoted cell apoptosis, while exhibited little effect on the cell cycle. We further found that 10 μM TAM could remarkably reduce the protein expression of VEGF, while 10 μM MPA only induce a slight reduction. Strikingly, the combined treatment of TAM and MPA exhibited additive effect on the proliferation, cell cycle, apoptosis rate and VEGF expression of SKOV3/DDP cells. We found that TAM, MPA and their combined treatment exhibited significant inhibitory effect on the cisplatin-resistant ovarian cancer SKOV3/DDP cells. Hence, TAM and MPA could be potential cytotoxic drugs to treat cisplatin-resistant patients with advanced ovarian cancer.

  4. The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1α expression

    International Nuclear Information System (INIS)

    Xu, Wei; Guo, Ting; Zhang, Yan; Jiang, Xiaohong; Zhang, Yongxian; Zen, Ke; Yu, Bo; Zhang, Chen-Yu

    2011-01-01

    Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1α in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1α expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1α mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1α expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1α by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1α had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1α decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPARγ activation by a PPARγ antagonist GW9662 abolished the suppressive effects of PGC-1α on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1α were enhanced by a PPARγ agonist troglitazone. Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-1α expression. PGC-1α suppresses PDGF-induced VSMC migration through PPARγ coactivation and, consequently, p38 MAPK inhibition.

  5. Vascular Pathology And Osteoarthritis Population-based studies

    NARCIS (Netherlands)

    T.A. Hoeven (Theun)

    2014-01-01

    markdownabstract__Abstract__ Osteoarthritis (OA) is the most frequent joint disorder worldwide and causes a considerable burden of pain, disability, and ever increasing costs to society. Due to rapid ageing and the epidemic of obesity in western populations, prevalence of OA is expected

  6. Gap junction protein connexin43 exacerbates lung vascular permeability.

    Directory of Open Access Journals (Sweden)

    James J O'Donnell

    Full Text Available Increased vascular permeability causes pulmonary edema that impairs arterial oxygenation and thus contributes to morbidity and mortality associated with Acute Respiratory Distress Syndrome and sepsis. Although components of intercellular adhesive and tight junctions are critical for maintaining the endothelial barrier, there has been limited study of the roles of gap junctions and their component proteins (connexins. Since connexins can modulate inflammatory signaling in other systems, we hypothesized that connexins may also regulate pulmonary endothelial permeability. The relationships between connexins and the permeability response to inflammatory stimuli were studied in cultured human pulmonary endothelial cells. Prolonged treatment with thrombin, lipopolysaccharide, or pathological cyclic stretch increased levels of mRNA and protein for the major connexin, connexin43 (Cx43. Thrombin and lipopolysaccharide both increased intercellular communication assayed by transfer of microinjected Lucifer yellow. Although thrombin decreased transendothelial resistance in these cells, the response was attenuated by pretreatment with the connexin inhibitor carbenoxolone. Additionally, the decreases of transendothelial resistance produced by either thrombin or lipopolysaccharide were attenuated by reducing Cx43 expression by siRNA knockdown. Both carbenoxolone and Cx43 knockdown also abrogated thrombin-induced phosphorylation of myosin light chain. Taken together, these data suggest that increased lung vascular permeability induced by inflammatory conditions may be amplified via increased expression of Cx43 and intercellular communication among pulmonary endothelial cells.

  7. Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice.

    Science.gov (United States)

    Paouri, Evi; Tzara, Ourania; Kartalou, Georgia-Ioanna; Zenelak, Sofia; Georgopoulos, Spiros

    2017-05-17

    Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in β-amyloid clearance. SIGNIFICANCE STATEMENT Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a

  8. Inhibition of the ERK phosphorylation plays a role in terbinafine-induced p21 up-regulation and DNA synthesis inhibition in human vascular endothelial cells

    International Nuclear Information System (INIS)

    Ho, P.-Y.; Hsu, S.-P.; Liang, Y.-C.; Kuo, M.-L.; Ho, Y.-S.; Lee, W.-S.

    2008-01-01

    Previously, we showed that terbinafine (TB) induces cell-cycle arrest in cultured human umbilical vein endothelial cells (HUVEC) through an up-regulation of the p21 protein. The aim of this study is to delineate the molecular mechanisms underlying TB-induced increase of p21 protein. RT-PCR analysis demonstrated that the mRNA levels of p21 and p53 were increased in the TB-treated HUVEC. The p21 promoter activity was also increased by TB treatment. Transfection of HUVEC with p53 dominant negative (DN) abolished the TB-induced increases of p21 promoter activity and protein level, suggesting that the TB-induced increase of p21 is p53-dependent. Western blot analysis demonstrated that TB decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK). Over-expression of mitogen-activated protein kinase (MEK)-1, the immediate upstream activator kinase of ERK, abolished the TB-induced increases of p21 and p53 protein and decrease of thymidine incorporation. The ERK inhibitor (PD98059) enhanced the TB-induced inhibition of thymidine incorporation into HUVEC. Taken together, these data suggest that the decrease of ERK activity plays a role in the TB-induced up-regulation of p21 in HUVEC. On the other hand, pretreatment of the cells with geranylgeraniol (GGOH), farnesol (FOH), or Ras inhibitor peptide did not affect the TB-induced decrease of thymidine incorporation. Taken together, our results suggest that TB might cause a decrease of MEK, which in turn up-regulates p53 through the inhibition of ERK phosphorylation, and finally causes an increase of p21 expression and cell-cycle arrest

  9. UAP56 is an important mediator of Angiotensin II/platelet derived growth factor induced vascular smooth muscle cell DNA synthesis and proliferation

    International Nuclear Information System (INIS)

    Sahni, Abha; Wang, Nadan; Alexis, Jeffrey

    2013-01-01

    Highlights: ► Knockdown of UAP56 inhibits Angiotensin II/PDGF induced vascular smooth muscle cell proliferation. ► UAP56 is a positive regulator of E2F transcriptional activation. ► UAP56 is present in the vessel wall of low flow carotid arteries. -- Abstract: Angiotensin (Ang) II and platelet-derived growth factor (PDGF) are important mediators of pathologic vascular smooth muscle cell (VSMC) proliferation. Identifying downstream mediators of Ang II and PDGF signaling may provide insights for therapies to improve vascular proliferative diseases. We have previously demonstrated that breakpoint cluster region (Bcr) is an important mediator of Ang II/PDGF signaling in VSMC. We have recently reported that the DExD/H box protein UAP56 is an interacting partner of Bcr in regulating VSMC DNA synthesis. We hypothesized that UAP56 itself is an important regulator of VSMC proliferation. In this report we demonstrate that knockdown of UAP56 inhibits Ang II/PDGF induced VSMC DNA synthesis and proliferation, and inhibits E2F transcriptional activity. In addition, we demonstrate that UAP56 is present in the vessel wall of low-flow carotid arteries. These findings suggest that UAP56 is a regulator of VSMC proliferation and identify UAP56 as a target for preventing vascular proliferative disease

  10. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

    Science.gov (United States)

    Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

    2009-12-01

    Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with

  11. Vascular nanomedicine: Site specific delivery of elastin stabilizing therapeutics to damaged arteries

    Science.gov (United States)

    Sinha, Aditi

    Elastin, a structural protein in the extra-cellular matrix, plays a critical role in the normal functioning of blood vessels. Apart from performing its primary function of providing resilience to arteries, it also plays major role in regulating cell-cell and cell-matrix interactions, response to injury, and morphogenesis. Medial arterial calcification (MAC) and abdominal aortic aneurysm (AAA) are two diseases where the structural and functional integrity of elastin is severely compromised. Although the clinical presentation of MAC and AAA differ, they have one common underlying causative mechanism---pathological degradation of elastin. Hence prevention of elastin degradation in the early stages of MAC and AAA can mitigate, partially if not wholly, the fatal consequences of both the diseases. The work presented here is motivated by the overwhelming statistics of people afflicted by elastin associated cardiovascular diseases and the unavailability of cure for the same. Overall goal of our research is to understand role of elastin degradation in cardiovascular diseases and to develop a targeted vascular drug delivery system that is minimally invasive, biodegradable, and non-toxic, that prevents elastin from degradation. Our hope is that such treatment will also help regenerate elastin, thereby providing a multi-fold treatment option for elasto-degenerative vascular diseases. For this purpose, we have first confirmed the combined role of degraded elastin and hyperglycemia in the pathogenesis of MAC. We have shown that in the absence of degraded elastin and TGF-beta1 (abundantly present in diabetic arteries) vascular smooth muscle cells maintain their homeostatic state, regardless of environmental glucose concentrations. However simultaneous exposure to glucose, elastin peptides and TGF-beta1 causes the pathological transgenesis of vascular cells to osteoblast-like cells. We show that plant derived polyphenols bind to vascular elastin with great affinity resulting in

  12. IGF-I Stimulates Cooperative Interaction between the IGF-I Receptor and CSK Homologous Kinase that Regulates SHPS-1 Phosphorylation in Vascular Smooth Muscle Cells

    Science.gov (United States)

    Radhakrishnan, Yashwanth; Shen, Xinchun; Maile, Laura A.; Xi, Gang

    2011-01-01

    IGF-I plays an important role in smooth muscle cell proliferation and migration. In vascular smooth muscle cells cultured in 25 mm glucose, IGF-I stimulated a significant increase in Src homology 2 domain containing protein tyrosine phosphatase substrate-1 (SHPS-1) phosphorylation compared with 5 mm glucose and this increase was required for smooth muscle cell proliferation. A proteome-wide screen revealed that carboxyl-terminal SRC kinase homologous kinase (CTK) bound directly to phosphotyrosines in the SHPS-1 cytoplasmic domain. Because the kinase(s) that phosphorylates these tyrosines in response to IGF-I is unknown, we determined the roles of IGF-I receptor (IGF-IR) and CTK in mediating SHPS-1 phosphorylation. After IGF-I stimulation, CTK was recruited to IGF-IR and subsequently to phospho-SHPS-1. Expression of an IGF-IR mutant that eliminated CTK binding reduced CTK transfer to SHPS-1, SHPS-1 phosphorylation, and cell proliferation. IGF-IR phosphorylated SHPS-1, which provided a binding site for CTK. CTK recruitment to SHPS-1 resulted in a further enhancement of SHPS-1 phosphorylation. CTK knockdown also impaired IGF-I-stimulated SHPS-1 phosphorylation and downstream signaling. Analysis of specific tyrosines showed that mutation of tyrosines 428/452 in SHPS-1 to phenylalanine reduced SHPS-1 phosphorylation but allowed CTK binding. In contrast, the mutation of tyrosines 469/495 inhibited IGF-IR-mediated the phosphorylation of SHPS-1 and CTK binding, suggesting that IGF-IR phosphorylated Y469/495, allowing CTK binding, and that CTK subsequently phosphorylated Y428/452. Based on the above findings, we conclude that after IGF-I stimulation, CTK is recruited to IGF-IR and its recruitment facilitates CTK's subsequent association with phospho-SHPS-1. This results in the enhanced CTK transfer to SHPS-1, and the two kinases then fully phosphorylate SHPS-1, which is necessary for IGF-I stimulated cellular proliferation. PMID:21799000

  13. NF1 Signal Transduction and Vascular Dysfunction

    Science.gov (United States)

    2015-05-01

    microenvironment that promotes much of the pathology associated with the disease . Moreover we hypothesize that a mechanistic consequence of the loss...obliteration of the normal red pulp architecture. In addition, we found significant peri-aveolar and peri-vascular inflammatory infiltrates in the lung...the mouse model of NF1 disease in the endothelium we proposed and have done experiments investigating the loss of endothelial NF1 in the adult

  14. Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

    Science.gov (United States)

    Zhang, Yixuan; Li, Qiang; Youn, Ji Youn; Cai, Hua

    2017-01-01

    The VEGF/VEGFR2/Akt/eNOS/NO pathway is essential to VEGF-induced angiogenesis. We have previously discovered a novel role of calpain in mediating VEGF-induced PI3K/AMPK/Akt/eNOS activation through Ezrin. Here, we sought to identify possible feedback regulation of VEGFR2 by calpain via its substrate protein phosphotyrosine phosphatase 1B (PTP1B), and the relevance of this pathway to VEGF-induced angiogenesis, especially in diabetic wound healing. Overexpression of PTP1B inhibited VEGF-induced VEGFR2 and Akt phosphorylation in bovine aortic endothelial cells, while PTP1B siRNA increased both, implicating negative regulation of VEGFR2 by PTP1B. Calpain inhibitor ALLN induced VEGFR2 activation, which can be completely blocked by PTP1B overexpression. Calpain activation induced by overexpression or Ca/A23187 resulted in PTP1B cleavage, which can be blocked by ALLN. Moreover, calpain activation inhibited VEGF-induced VEGFR2 phosphorylation, which can be restored by PTP1B siRNA. These data implicate calpain/PTP1B negative feedback regulation of VEGFR2, in addition to the primary signaling pathway of VEGF/VEGFR2/calpain/PI3K/AMPK/Akt/eNOS. We next examined a potential role of PTP1B in VEGF-induced angiogenesis. Endothelial cells transfected with PTP1B siRNA showed faster wound closure in response to VEGF. Aortic discs isolated from PTP1B siRNA-transfected mice also had augmented endothelial outgrowth. Importantly, PTP1B inhibition and/or calpain overexpression significantly accelerated wound healing in STZ-induced diabetic mice. In conclusion, our data for the first time demonstrate a calpain/PTP1B/VEGFR2 negative feedback loop in the regulation of VEGF-induced angiogenesis. Modulation of local PTP1B and/or calpain activities may prove beneficial in the treatment of impaired wound healing in diabetes. PMID:27872190

  15. Pathology of radiation induced lung damage

    International Nuclear Information System (INIS)

    Kawabata, Yoshinori; Murata, Yoshihiko; Ogata, Hideo; Katagiri, Shiro; Sugita, Hironobu; Iwai, Kazuo; Sakurai, Isamu.

    1985-01-01

    We examined pathological findings of radiation induced lung damage. Twenty-three cases are chosen from our hospital autopsy cases for 9 years, which fulfil strict criteria of radiation lung damage. Lung damage could be classified into 3 groups : 1) interstitial pneumonia type (9 cases), 2) intermediate pneumonia type (8 cases), and 3) alveolar pneumonia type (6 cases), according to the degree of intra-luminal exudation. These classification is well correlated with clinical findings. Pathological alveolar pneumonia type corresponds to symptomatic, radiologic ground glass pneumonic shadow. And pathologic interstitial type corresponds to clinical asymptomatic, radiologic reticulo-nodular shadow. From the clinico-pathological view point these classification is reasonable one. Radiation affects many lung structures and showed characteristic feature of repair. Elastofibrosis of the alveolar wall is observed in every cases, obstructive bronchiolitis are observed in 5 cases, and obstructive bronchiolitis in 9 cases. They are remarkable additional findings. Thickening of the interlobular septum, broncho-vascular connective tissue, and pleural layer are observed in every cases together with vascular lesions. (author)

  16. Increased expression of matrix metalloproteinase-1 in systemic vessels of preeclamptic women: a critical mediator of vascular dysfunction.

    Science.gov (United States)

    Estrada-Gutierrez, Guadalupe; Cappello, Renato E; Mishra, Nikita; Romero, Roberto; Strauss, Jerome F; Walsh, Scott W

    2011-01-01

    This study was conducted to determine the following: (1) whether matrix metalloproteinase-1 (MMP-1) is increased in systemic vessels of preeclamptic women, (2) whether this increase might be mediated by neutrophils, and (3) whether MMP-1 could be responsible for vascular dysfunction. Omental arteries and plasma were collected from healthy pregnant and preeclamptic women. Omental arteries were evaluated for gene and protein expression of MMP-1, collagen type 1α, tissue inhibitor of metalloproteinase-1, and vascular reactivity to MMP-1. Gene and protein expression levels were also evaluated in human vascular smooth muscle cells (VSMCs) co-cultured with activated neutrophils, reactive oxygen species, or tumor necrosis factor α. Vessel expression of MMP-1 and circulating MMP-1 levels were increased in preeclamptic women, whereas vascular expression of collagen or tissue inhibitor of metalloproteinase-1 were down-regulated or unchanged. In cultured VSMCs, the imbalance in collagen-regulating genes of preeclamptic vessels was reproduced by treatment with neutrophils, tumor necrosis factor α, or reactive oxygen species. Chemotaxis studies with cultured cells revealed that MMP-1 promoted recruitment of neutrophils via vascular smooth muscle release of interleukin-8. Furthermore, MMP-1 induced vasoconstriction via protease-activated receptor-1, whose expression was significantly increased in omental arteries of preeclamptic women and in VSMCs co-cultured with neutrophils. Collectively, these findings disclose a novel role for MMP-1 as a mediator of vasoconstriction and vascular dysfunction in preeclampsia. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Muscular pathology: echographic and NMR imaging aspects

    International Nuclear Information System (INIS)

    Pascal-Suisse, P.; Beaurain, P.; Mougniot, C.

    1995-01-01

    A comparison of echographic techniques and NMR imaging has been done for the diagnosis of muscular trauma and tumor pathologies. In traumatic pathology, the echographic analysis allows to determine the complete assessment of recent muscular injuries. NMR imaging can be used in granuloma or fibrous callosity appreciation and for the analysis of deep injury (muscles and muscles-tendon junctions) and of muscular aponeurosis. Echography must be used together with color coding Doppler technique in the diagnosis of tumor pathology and for the study of slow fluxes. The recently available energy Doppler technique seems to be powerful in the study of vascularization of small expansive formations, but their extension to adjacent bone or tissue can only be appreciated using NMR imaging. (J.S.)

  18. Pathology Assistant (C - Gamechanger Of Pathology Diagnostic

    Directory of Open Access Journals (Sweden)

    Asel Kudaybergenova

    2016-06-01

    When the competition ended, we received many favor- able reviews and we decided to start another project a little bit similar to the competition. Every month we show three interesting and difficult to diagnose cases provided by the leading Russian pathologists. The participants can look through the clinical data and digitized histological slides, and then discuss what they see among their professional society. There are 400  specialists  from  post  USSR countries.  Moreover, we get a few proposal of partnership to start a similar project in EU. And the last product in line is Pathology Assistant. It is a game changer. Pathology Assistant is a Digital Pathology©technology driven application for pathology diagnostics, tool to innovate pathology diagnostics in more simple, proven by analytical algo- rithm, automatically delivering anticipated support way. The service provides vast and structured database of validated cases, intuitive interface, fast and convenient system of analytical search. Pathology Assistant will streamline and simplify pathologist’s way to the right decision. Pathologists from Memorial Sloan Catering and biggest EU labs are working on preparing the con- tent for the project.  

  19. Irradiation-induced regulation of plasminogen activator inhibitor type-1 and vascular endothelial growth factor in six human squamous cell carcinoma lines of the head and neck

    International Nuclear Information System (INIS)

    Artman, Meri Tuuli

    2014-01-01

    Radiation therapy is frequently used to treat squamous cell carcinoma of the head and neck (SCCHN), although, it can be unsuccessful due to radiation resistance of the tumor. Currently, there are no established predictive markers for radiation resistance in SCCHN. The aim of this work was to investigate PAI-1 and VEGF secretion as markers for radiation resistance in six human SCCHN cell lines. The cell lines differed in their basal secretion levels and in their in vitro radiation sensitivity. PAI-1 and VEGF levels increased after irradiation in a dose-dependent manner. A significant correlation was detected between radiation-induced PAI-1 and VEGF secretion, which suggests that irradiation-induced secretion of PAI-1 and VEGF are partially regulated by related mechanisms. However, neither basal levels nor radiation-induced PAI-1 and VEGF secretion correlated with radiation resistance. Therefore, PAI-1 and VEGF are most likely not predictive markers for radiation resistance in SCCHN.

  20. Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection

    Science.gov (United States)

    Kemper, Martin F.; Stirone, Chris; Krause, Diana N.; Duckles, Sue P.; Procaccio, Vincent

    2014-01-01

    We previously found that estrogen exerts a novel protective effect on mitochondria in brain vasculature. Here we demonstrate in rat cerebral blood vessels that 17β-estradiol (estrogen), both in vivo and ex vivo, affects key transcriptional coactivators responsible for mitochondrial regulation. Treatment of ovariectomized rats with estrogen in vivo lowered mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) but increased levels of the other PGC-1 isoforms: PGC-1β and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1α via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1α downregulation. In contrast to the decrease in PGC-1α, estrogen increased protein levels of nuclear respiratory factor 1, a known PGC target and mediator of mitochondrial biogenesis. The latter effect of estrogen was independent of PI3K, suggesting a separate mechanism consistent with increased expression of PGC-1β and PRC. We demonstrated increased mitochondrial biogenesis following estrogen treatment in vivo; cerebrovascular levels of mitochondrial transcription factor A and electron transport chain subunits as well as the mitochondrial/ nuclear DNA ratio were increased. We examined a downstream target of PGC-1β, glutamate-cysteine ligase (GCL), the rate-limiting enzyme for glutathione synthesis. In vivo estrogen increased protein levels of both GCL subunits and total glutathione levels. Together these data show estrogen differentially regulates PGC-1 isoforms in brain vasculature, underscoring the importance of these coactivators in adapting mitochondria in specific tissues. By upregulating PGC-1β and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection. PMID:24275351

  1. Targeted modulation of reactive oxygen species in the vascular endothelium

    OpenAIRE

    Shuvaev, Vladimir V.; Muzykantov, Vladimir R.

    2011-01-01

    Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-mo...

  2. Brain Arterial Diameters as a Risk Factor for Vascular Events

    OpenAIRE

    Gutierrez, Jose; Cheung, Ken; Bagci, Ahmet; Rundek, Tatjana; Alperin, Noam; Sacco, Ralph L; Wright, Clinton B; Elkind, Mitchell S V

    2015-01-01

    Background Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events. Methods and Results Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, ca...

  3. Speech-Language-Pathology and Audiology Handbook.

    Science.gov (United States)

    New York State Education Dept., Albany. Office of the Professions.

    The handbook contains State Education Department rules and regulations that govern speech-language pathology and audiology in New York State. The handbook also describes licensure and first registration as a licensed speech-language pathologist or audiologist. The introduction discusses professional regulation in New York State while the second…

  4. Nondiabetic retinal pathology - prevalence in diabetic retinopathy screening.

    Science.gov (United States)

    Nielsen, Nathan; Jackson, Claire; Spurling, Geoffrey; Cranstoun, Peter

    2011-07-01

    To determine the prevalence of photographic signs of nondiabetic retinal pathology in Australian general practice patients with diabetes. Three hundred and seven patients with diabetes underwent retinal photography at two general practices, one of which was an indigenous health centre. The images were assessed for signs of pathology by an ophthalmologist. Signs of nondiabetic retinal pathology were detected in 31% of subjects with adequate photographs. Features suspicious of glaucoma were detected in 7.7% of subjects. Other abnormalities detected included signs of age related macular degeneration (1.9%), epiretinal membranes (2.4%), vascular pathology (9.6%), chorioretinal lesions (2.9%), and congenital disc anomalies (2.9%). Indigenous Australian patients were more likely to have signs of retinal pathology and glaucoma. Signs of nondiabetic retinal pathology were frequently encountered. In high risk groups, general practice based diabetic retinopathy screening may reduce the incidence of preventable visual impairment, beyond the benefits of detection of diabetic retinopathy alone.

  5. Extracellular Matrix Molecules Facilitating Vascular Biointegration

    Directory of Open Access Journals (Sweden)

    Martin K.C. Ng

    2012-08-01

    Full Text Available All vascular implants, including stents, heart valves and graft materials exhibit suboptimal biocompatibility that significantly reduces their clinical efficacy. A range of biomolecules in the subendothelial space have been shown to play critical roles in local regulation of thrombosis, endothelial growth and smooth muscle cell proliferation, making these attractive candidates for modulation of vascular device biointegration. However, classically used biomaterial coatings, such as fibronectin and laminin, modulate only one of these components; enhancing endothelial cell attachment, but also activating platelets and triggering thrombosis. This review examines a subset of extracellular matrix molecules that have demonstrated multi-faceted vascular compatibility and accordingly are promising candidates to improve the biointegration of vascular biomaterials.

  6. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  7. Diffuse and vascular hepatic diseases

    International Nuclear Information System (INIS)

    Kreimeyer, S.; Grenacher, L.

    2011-01-01

    In addition to focal liver lesions, diffuse and vascular disorders of the liver represent a wide spectrum of liver diseases which are from the radiological point of view often difficult or nearly impossible to diagnose. Classical diagnostic methods are computed tomography and magnetic resonance imaging in addition to ultrasound. Diffuse parenchymal damage caused by diseases of various etiologies is therefore difficult to evaluate because it often lacks characteristic morphological features. For hepatic steatosis, hemochromatosis/siderosis as an example of a diffuse storage disease and sarcoidosis and candidiasis as infectious/inflammatory diseases, an image-based diagnosis is appropriate in some cases. For most diffuse liver diseases, however only nonspecific changes are visualized. Vascular pathologies of the liver, such as the Budd-Chiari syndrome and portal vein thrombosis, however, can usually be diagnosed very clearly using radiology and there is also a very effective interventional radiological treatment. Chronic diseases very often culminate in liver cirrhosis which is highly associated with an increased risk of liver cancer. (orig.) [de

  8. Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica.

    Science.gov (United States)

    Zelko, Igor N; Zhu, Jianxin; Ritzenthaler, Jeffrey D; Roman, Jesse

    2016-11-28

    Occupational and environmental exposure to crystalline silica may lead to the development of silicosis, which is characterized by inflammation and progressive fibrosis. A substantial number of patients diagnosed with silicosis develop pulmonary hypertension. Pulmonary hypertension associated with silicosis and with related restrictive lung diseases significantly reduces survival in affected subjects. An animal model of silicosis has been described previously however, the magnitude of vascular remodeling and hemodynamic effects of inhaled silica are largely unknown. Considering the importance of such information, this study investigated whether mice exposed to silica develop pulmonary hypertension and vascular remodeling. C57BL6 mice were intratracheally injected with either saline or crystalline silica at doses 0.2 g/kg, 0.3 g/kg and 0.4 g/kg and then studied at day 28 post-exposure. Pulmonary hypertension was characterized by changes in right ventricular systolic pressure and lung histopathology. Mice exposed to saline showed normal lung histology and hemodynamic parameters while mice exposed to silica showed increased right ventricular systolic pressure and marked lung pathology characterized by a granulomatous inflammatory reaction and increased collagen deposition. Silica-exposed mice also showed signs of vascular remodeling with pulmonary artery muscularization, vascular occlusion, and medial thickening. The expression of pro-inflammatory genes such as TNF-α and MCP-1 was significantly upregulated as well as the expression of the pro-remodeling genes collagen type I, fibronectin and the metalloproteinases MMP-2 and TIMP-1. On the other hand, the expression of several vasculature specific genes involved in the regulation of endothelial function was significantly attenuated. We characterized a new animal model of pulmonary hypertension secondary to pulmonary fibrosis induced by crystalline silica. Our data suggest that silica promotes the damage of the

  9. Management of vascular anomalies: Review of institutional management algorithm

    Directory of Open Access Journals (Sweden)

    Lalit K Makhija

    2017-01-01

    Full Text Available Introduction: Vascular anomalies are congenital lesions broadly categorised into vascular tumour (haemangiomas and vascular dysmorphogenesis (vascular malformation. The management of these difficult problems has lately been simplified by the biological classification and multidisciplinary approach. To standardise the treatment protocol, an algorithm has been devised. The study aims to validate the algorithm in terms of its utility and presents our experience in managing vascular anomalies. Materials and Methods: The biological classification of Mulliken and Glowacki was followed. A detailed algorithm for management of vascular anomalies has been devised in the department. The protocol is being practiced by us since the past two decades. The data regarding the types of lesions and treatment modality used were maintained. Results and Conclusion: This study was conducted from 2002 to 2012. A total of 784 cases of vascular anomalies were included in the study of which 196 were haemangiomas and 588 were vascular malformations. The algorithmic approach has brought an element of much-needed objectivity in the management of vascular anomalies. This has helped us to define the management of particular lesion considering its pathology, extent and aesthetic and functional consequences of ablation to a certain extent.

  10. Pathological narcissism and the obstruction of love.

    Science.gov (United States)

    Kealy, David; Ogrodniczuk, John S

    2014-03-01

    Pathological narcissism is a form of maladaptive self-regulation that impedes the capacity to love. Although narcissism is often construed as excessive self-love, individuals with pathological narcissism are impaired in being able to love themselves as well as others. With the subject of impaired love in mind, we review selected conceptualizations from an enormous and diverse psychodynamic literature on narcissism. Major theoretical approaches illustrate a number of psychodynamics associated with narcissistic self-regulatory problems. This paper provides a concise overview of major conceptual themes regarding pathological narcissism and impaired capacity to love.

  11. Pathology in Greece.

    Science.gov (United States)

    Sakellariou, S; Patsouris, E

    2015-11-01

    Pathology is the field of medicine that studies diseases. Ancient Greece hosted some of the earliest societies that laid the structural foundations of pathology. Initially, knowledge was based on observations but later on the key elements of pathology were established based on the dissection of animals and the autopsy of human cadavers. Christianized Greece under Ottoman rule (1453-1821) was not conducive to the development of pathology. After liberation, however, a series of events took place that paved the way for the establishment and further development of the specialty. The appointment in 1849 of two Professors of Pathology at the Medical School of Athens for didactical purposes proved to be the most important step in fostering the field of pathology in modern Greece. Presently in Greece there are seven university departments and 74 pathology laboratories in public hospitals, employing 415 specialized pathologists and 90 residents. The First Department of Pathology at the Medical School of Athens University is the oldest (1849) and largest in Greece, encompassing most pathology subspecialties.

  12. Interleukin-22: immunobiology and pathology

    Science.gov (United States)

    Dudakov, Jarrod A.; Hanash, Alan M.; van den Brink, Marcel R.M.

    2015-01-01

    Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T-helper (Th)-17 cells, γδ T cells, NKT cells and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has rapidly evolved since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues including the intestines, lung, liver, kidney, thymus, pancreas and skin. IL-22 primarily targets non-hematopoietic epithelial and stromal cells where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we will assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. PMID:25706098

  13. Systemic Hypoxia Changes the Organ-Specific Distribution of Vascular Endothelial Growth Factor and Its Receptors

    Science.gov (United States)

    Marti, Hugo H.; Risau, Werner

    1998-12-01

    Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. Here we demonstrate that VEGF is induced in vivo by exposing mice to systemic hypoxia. VEGF induction was highest in brain, but also occurred in kidney, testis, lung, heart, and liver. In situ hybridization analysis revealed that a distinct subset of cells within a given organ, such as glial cells and neurons in brain, tubular cells in kidney, and Sertoli cells in testis, responded to the hypoxic stimulus with an increase in VEGF expression. Surprisingly, however, other cells at sites of constitutive VEGF expression in normal adult tissues, such as epithelial cells in the choroid plexus and kidney glomeruli, decreased VEGF expression in response to the hypoxic stimulus. Furthermore, in addition to VEGF itself, expression of VEGF receptor-1 (VEGFR-1), but not VEGFR-2, was induced by hypoxia in endothelial cells of lung, heart, brain, kidney, and liver. VEGF itself was never found to be up-regulated in endothelial cells under hypoxic conditions, consistent with its paracrine action during normoxia. Our results show that the response to hypoxia in vivo is differentially regulated at the level of specific cell types or layers in certain organs. In these tissues, up- or down-regulation of VEGF and VEGFR-1 during hypoxia may influence their oxygenation after angiogenesis or modulate vascular permeability.

  14. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

    Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

    2000-01-01

    The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer....

  15. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

    Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

    2000-01-01

    The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer....

  16. Advanced Maternal Age Worsens Postpartum Vascular Function

    Directory of Open Access Journals (Sweden)

    Jude S. Morton

    2017-06-01

    Full Text Available The age at which women experience their first pregnancy has increased throughout the decades. Pregnancy has an important influence on maternal short- and long-term cardiovascular outcomes. Pregnancy at an advanced maternal age increases maternal risk of gestational diabetes, preeclampsia, placenta previa and caesarian delivery; complications which predict worsened cardiovascular health in later years. Aging also independently increases the risk of cardiovascular disease; therefore, combined risk in women of advanced maternal age may lead to detrimental cardiovascular outcomes later in life. We hypothesized that pregnancy at an advanced maternal age would lead to postpartum vascular dysfunction. We used a reproductively aged rat model to investigate vascular function in never pregnant (virgin, previously pregnant (postpartum and previously mated but never delivered (nulliparous rats at approximately 13.5 months of age (3 months postpartum or equivalent. Nulliparous rats, in which pregnancy was spontaneously lost, demonstrated significantly reduced aortic relaxation responses (methylcholine [MCh] Emax: 54.2 ± 12.6% vs. virgin and postpartum rats (MCh Emax: 84.8 ± 3.5% and 84.7 ± 3.2% respectively; suggesting pregnancy loss causes a worsened vascular pathology. Oxidized LDL reduced relaxation to MCh in aorta from virgin and postpartum, but not nulliparous rats, with an increased contribution of the LOX-1 receptor in the postpartum group. Further, in mesenteric arteries from postpartum rats, endothelium-derived hyperpolarization (EDH-mediated vasodilation was reduced and a constrictive prostaglandin effect was apparent. In conclusion, aged postpartum rats exhibited vascular dysfunction, while rats which had pregnancy loss demonstrated a distinct vascular pathology. These data demonstrate mechanisms which may lead to worsened outcomes at an advanced maternal age; including early pregnancy loss and later life cardiovascular dysfunction.

  17. Atlas of neuroanatomy with radiologic correlation and pathologic illustration

    International Nuclear Information System (INIS)

    Dublin, A.B.; Dublin, W.B.

    1982-01-01

    This atlas correlates gross neuroanatomic specimens with radiographs and computed tomographic scans. Pathologic specimens and radiographs are displayed in a similar manner. The first chapter, on embryology, shows the development of the telencephalon, diencephalon, mesencephalon, and metencephalon through a series of overlays. The anatomical section shows the surface of the brain, the ventricles and their adjacent structures, and the vascular system. CT anatomy is demonstrated by correlating CT scans with pathologic brain specimens cut in the axial plane. Pathologic changes associated with congenital malformations, injections, injuries, tumors, and other causes are demonstrated in the last six chapters

  18. Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

    Science.gov (United States)

    Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

    2010-05-14

    Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

  19. Brain Arterial Diameters as a Risk Factor for Vascular Events.

    Science.gov (United States)

    Gutierrez, Jose; Cheung, Ken; Bagci, Ahmet; Rundek, Tatjana; Alperin, Noam; Sacco, Ralph L; Wright, Clinton B; Elkind, Mitchell S V

    2015-08-06

    Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events. Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, called the brain arterial remodeling (BAR) score, was obtained by averaging the measured diameters within each individual. Individuals with a BAR score -2 and 2 SDs had the largest diameters. All vascular events were recorded prospectively after the brain magnetic resonance imaging. Spline curves and incidence rates were used to test our hypothesis. The association of the BAR score with death (P=0.001), vascular death (P=0.02), any vascular event (P=0.05), and myocardial infarction (P=0.10) was U-shaped except for ischemic stroke (P=0.74). Consequently, incidence rates for death, vascular death, myocardial infarction, and any vascular event were higher in individuals with the largest diameters, whereas individuals with the smallest diameters had a higher incidence of death, vascular death, any vascular event, and ischemic stroke compared with individuals with average diameters. The risk of death, vascular death, and any vascular event increased at both extremes of brain arterial diameters. The pathophysiology linking brain arterial remodeling to systemic vascular events needs further research. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  20. Pathological gambling and criminality.

    Science.gov (United States)

    Folino, Jorge Oscar; Abait, Patricia Estela

    2009-09-01

    To review research results on the relationship between pathological gambling and criminality, published in 2007 and 2008, in English and in Spanish. An important association between pathological gambling and criminality was confirmed in populations of anonymous gamblers, helpline callers and substance abusers. Helplines provide a timely service to gamblers who have not reached the maximum stages in the development of a pathological gambling pattern. Pathological gambling is associated with violence in couples and dysfunctional families. Inversely, violence is also an antecedent promoting vulnerability toward pathological gambling. Impulsiveness shows diverse relationships with pathological gambling and violence as well. A pathological gambler's involvement in crime is exceptionally considered without responsibility by justice, but it may be an indicator of the disorder severity and the need for special therapeutic tactics. While reviewing the present study, research work was published that contributed to a better understanding of the association between pathological gambling and criminality and went further into their complex relationship and the formulation of explanatory models related to impulsiveness.

  1. Radiographic pathology for technologists

    International Nuclear Information System (INIS)

    Mace, J.D.; Kowalczyk, N.

    1988-01-01

    This book explains the fundamentals of disease mechanisms and relates this to the practice of radiologic science. Each chapter begins with a discussion of normal anatomy and physiology, then covers pathology and demonstrates how the pathology appears on film. Imaging modalities such as computed tomography, MRI, and ultrasound are also discussed. Clinical case studies are included

  2. Pathology annual. Part 2

    International Nuclear Information System (INIS)

    Rosen, P.P.

    1987-01-01

    This book contains 11 selections. Some of the titles are: Applications of in situ DNA hybridization technology to diagnostic surgical pathology; Neoplasms associated with immune deficiencies; Chronic gastritis: The pathologists's role; Necrosis in lymph nodes; Pathologic changes of osteochondrodysplasia in infancy: A review; and Immunoglobulin light chain nephropathies

  3. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

    International Nuclear Information System (INIS)

    Shibuya, Masabumi; Claesson-Welsh, Lena

    2006-01-01

    The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases

  4. The Nun Study: risk factors for pathology and clinical-pathologic correlations.

    Science.gov (United States)

    Mortimer, James A

    2012-07-01

    The Nun Study was the first cohort study to enroll and follow a large, well-defined population that included demented and non-demented participants, all of whom agreed to donate their brains for research. The inclusion of systematic neuropathologic analysis in this study has resulted in a greater understanding of the role of Alzheimer and vascular pathology in the expression of memory deficits and dementia and has provided data showing that biomarkers for the pathology may be evident many decades earlier in adult life. Findings related to neuropathology in this study have included the following: (1) Although clinical outcomes were strongly correlated with Alzheimer neuropathology, about one-third of the participants fulfilling criteria for neuropathologic Alzheimer's disease (AD) were not demented at the time of death. (2) Brain infarcts by themselves had little effect on cognitive status, but played an important role in increasing the risk of dementia associated with Alzheimer pathology. (3) Hippocampal volume was strongly correlated with Braak neurofibrillary stage even in participants with normal cognitive function. (4) A linguistic characteristic of essays written in early adult life, idea density, had a strong association with not only clinical outcomes in late life, but the severity of Alzheimer neuropathology as well. (5) The effect of apolipoprotein E-e4 on dementia was mediated through Alzheimer, but not vascular pathology.

  5. Pancreatic transplantation: Radiologic evaluation of vascular complications

    International Nuclear Information System (INIS)

    Snider, J.F.; Hunter, D.W.; Kuni, C.C.; Castaneda-Zuniga, W.R.; Letourneau, J.G.

    1991-01-01

    Transplantation of the pancreas is an increasingly common therapeutic option for preventing or delaying complications of type I diabetes mellitus. The authors studied the relative roles of various radiologic examinations in diagnosing vascular complications in these grafts including arterial and venous thrombosis, stenosis, and anastomotic leak (the most common vascular factors that necessitate pancreatectomy of the transplant), as defined with pathologic or arteriographic data. The results of 78 scintigraphic flow studies, 40 abdominal and pelvic computed tomographic (CT) scans, 27 sonograms, and eight color Doppler studies were evaluated in 52 patients who received a total of 27 cadaveric and 26 living-donor grafts over a 12-year period. These results were correlated with the data from 45 gross and microscopic pathologic studies and 37 arteriograms to determine their relative value in enabling detection of graft thrombosis and other vascular complications. Scintigraphy, CT, sonography, and color Doppler were all sensitive in detection of generalized graft abnormalities but lacked specificity in defining the underlying etiologic factors

  6. Pancreatic transplantation: Radiologic evaluation of vascular complications

    Energy Technology Data Exchange (ETDEWEB)

    Snider, J.F.; Hunter, D.W.; Kuni, C.C.; Castaneda-Zuniga, W.R.; Letourneau, J.G. (Univ. of Minnesota Hospital and Clinic, Minneapolis (USA))

    1991-03-01

    Transplantation of the pancreas is an increasingly common therapeutic option for preventing or delaying complications of type I diabetes mellitus. The authors studied the relative roles of various radiologic examinations in diagnosing vascular complications in these grafts including arterial and venous thrombosis, stenosis, and anastomotic leak (the most common vascular factors that necessitate pancreatectomy of the transplant), as defined with pathologic or arteriographic data. The results of 78 scintigraphic flow studies, 40 abdominal and pelvic computed tomographic (CT) scans, 27 sonograms, and eight color Doppler studies were evaluated in 52 patients who received a total of 27 cadaveric and 26 living-donor grafts over a 12-year period. These results were correlated with the data from 45 gross and microscopic pathologic studies and 37 arteriograms to determine their relative value in enabling detection of graft thrombosis and other vascular complications. Scintigraphy, CT, sonography, and color Doppler were all sensitive in detection of generalized graft abnormalities but lacked specificity in defining the underlying etiologic factors.

  7. Arterial vascularization of the pineal gland.

    Science.gov (United States)

    Kahilogullari, Gokmen; Ugur, Hasan Caglar; Comert, Ayhan; Brohi, Recep Ali; Ozgural, Onur; Ozdemir, Mevci; Karahan, Suleyman Tuna

    2013-10-01

    The arterial vascularization of the pineal gland (PG) remains a debatable subject. This study aims to provide detailed information about the arterial vascularization of the PG. Thirty adult human brains were obtained from routine autopsies. Cerebral arteries were separately cannulated and injected with colored latex. The dissections were carried out using a surgical microscope. The diameters of the branches supplying the PG at their origin and vascularization areas of the branches of the arteries were investigated. The main artery of the PG was the lateral pineal artery, and it originated from the posterior circulation. The other arteries included the medial pineal artery from the posterior circulation and the rostral pineal artery mainly from the anterior circulation. Posteromedial choroidal artery was an important artery that branched to the PG. The arterial supply to the PG was studied comprehensively considering the debate and inadequacy of previously published studies on this issue available in the literature. This anatomical knowledge may be helpful for surgical treatment of pathologies of the PG, especially in children who develop more pathology in this region than adults.

  8. Vascular Access in Children

    International Nuclear Information System (INIS)

    Krishnamurthy, Ganesh; Keller, Marc S.

    2011-01-01

    Establishment of stable vascular access is one of the essential and most challenging procedures in a pediatric hospital. Many clinical specialties provide vascular service in a pediatric hospital. At the top of the “expert procedural pyramid” is the pediatric interventional radiologist, who is best suited and trained to deliver this service. Growing awareness regarding the safety and high success rate of vascular access using image guidance has led to increased demand from clinicians to provide around-the-clock vascular access service by pediatric interventional radiologists. Hence, the success of a vascular access program, with the pediatric interventional radiologist as the key provider, is challenging, and a coordinated multidisciplinary team effort is essential for success. However, there are few dedicated pediatric interventional radiologists across the globe, and also only a couple of training programs exist for pediatric interventions. This article gives an overview of the technical aspects of pediatric vascular access and provides useful tips for obtaining vascular access in children safely and successfully using image guidance.

  9. Pediatric vascular access

    International Nuclear Information System (INIS)

    Donaldson, James S.

    2006-01-01

    Pediatric interventional radiologists are ideally suited to provide vascular access services to children because of inherent safety advantages and higher success from using image-guided techniques. The performance of vascular access procedures has become routine at many adult interventional radiology practices, but this service is not as widely developed at pediatric institutions. Although interventional radiologists at some children's hospitals offer full-service vascular access, there is little or none at others. Developing and maintaining a pediatric vascular access service is a challenge. Interventionalists skilled in performing such procedures are limited at pediatric institutions, and institutional support from clerical staff, nursing staff, and technologists might not be sufficiently available to fulfill the needs of such a service. There must also be a strong commitment by all members of the team to support such a demanding service. There is a slippery slope of expected services that becomes steeper and steeper as the vascular access service grows. This review is intended primarily as general education for pediatric radiologists learning vascular access techniques. Additionally, the pediatric or adult interventional radiologist seeking to expand services might find helpful tips. The article also provides education for the diagnostic radiologist who routinely interprets radiographs containing vascular access devices. (orig.)

  10. Vascular retraction driven by matrix softening

    Science.gov (United States)

    Valentine, Megan

    We recently discovered we can directly apply physical forces and monitor the downstream responses in a living organism in real time through manipulation of the blood vessels of a marine organism called, Botryllus schlosseri. The extracellular matrix (ECM) plays a key role in regulating vascular growth and homeostasis in Botryllus,a basal chordate which has a large, transparent extracorporeal vascular network that can encompass areas >100 cm2. We have determined that lysyl oxidase 1 (LOX1), which is responsible for cross-linking collagen, is expressed in all vascular cells and is critically important for vascular maintenance. Inhibition of LOX1 activity in vivo by the addition of a specific inhibitor, ß-aminopropionitrile (BAPN), caused a rapid, global regression of the entire vascular bed, with some vessels regressing >10 mm within 16 hrs. In this talk, I will discuss the molecular and cellular origins of this systemic remodeling event, which hinges upon the ability of the vascular cells to sense and respond to mechanical signals, while introducing this exciting new model system for studies of biological physics and mechanobiology. Collaborators: Anthony DeTomaso, Delany Rodriguez, Aimal Khankhel (UCSB).

  11. Vascular malformations in pediatrics

    International Nuclear Information System (INIS)

    Reith, W.; Shamdeen, M.G.

    2003-01-01

    Vascular malformations are the cause of nearly all non-traumatic intracranial hemorrhage in children beyond the neonatal stage. Therefore, any child presenting with spontaneous intracranial hemorrhage should be evaluated for child abuse and for vascular malformations. Intracerebral malformations of the cerebral vasculature include vein of Galen malformations, arteriovenous malformation (AVM), cavernomas, dural arteriovenous fistulas, venous anomalies (DVA), and capillary teleangiectasies. Although a few familial vascular malformation have been reported, the majority are sporadic. Clinical symptoms, diagnostic and therapeutic options are discussed. (orig.) [de

  12. Evaluation of the erectile dysfunction of vascular origin by means of the ultrasound Doppler Duplex

    International Nuclear Information System (INIS)

    Varon, Claudia; Aponte, Hernan Alonso; Poveda, Alvaro; Rubiano, Nicolas; Serrano, Adolfo

    1996-01-01

    We studied 20 patients with erectile dysfunction of vascular origin and 10 patients with psychological erectile dysfunction with Doppler ultrasound before and after injection of intra cavernous vasoactive substances. We observed that psychological erectile dysfunction, is characterized by normal vascular velocities in cavernous arteries (control group). In patients with vascular aetiology we obtained abnormal registrations that differentiated arterial from venous pathology. There was a significant difference in the diameter of the cavernous artery and the systolic flow after the injection of vasoactive substances

  13. Spinal vascular malformations in non-perimesencephalic subarachnoid hemorrhage

    NARCIS (Netherlands)

    Germans, M. R.; Pennings, F. A.; Sprengers, M. E. S.; Vandertop, W. P.

    2008-01-01

    OBJECTIVE: In patients with non-traumatic subarachnoid hemorrhage (SAH) and no evidence for a cerebral aneurysm on angiography, a frequent cause of the hemorrhage is perimesencephalic hemorrhage or other cerebral vascular pathology. In some patients no cause is found. The exact incidence of a spinal

  14. Childhood vascular Tumours in Benin City, Nigeria | Igbe | Annals of ...

    African Journals Online (AJOL)

    Background: Vasoformative tumours are one of the commonest tumours in childhood. The patterns of these tumours in Benin City, however, are not known. Objective: To determine the incidence and morphological patterns of childhood vascular tumours as seen in the Department of Pathology University of Benin Teaching ...

  15. Hippocampal diffusion tensor imaging microstructural changes in vascular dementia

    DEFF Research Database (Denmark)

    Ostojic, Jelena; Kozic, Dusko; Pavlovic, Aleksandra

    2015-01-01

    To explore microstructural integrity of hippocampus in vascular dementia (VD) using DTI. Twenty-five individuals with VD, without magnetic resonance imaging (MRI) evidence of gray matter pathology, and 25 matched healthy control (HC) individuals underwent a 3T MRI protocol including T2, FLAIR, an...

  16. VEGF signaling inside vascular endothelial cells and beyond.

    Science.gov (United States)

    Eichmann, Anne; Simons, Michael

    2012-04-01

    Vascular endothelial growth factor-A (VEGF-A) has long been recognized as the key regulator of vascular development and function in health and disease. VEGF is a secreted polypeptide that binds to transmembrane tyrosine kinase VEGF receptors on the plasma membrane, inducing their dimerization, activation and assembly of a membrane-proximal signaling complex. Recent studies have revealed that many key events of VEGFR signaling occur inside the endothelial cell and are regulated by endosomal receptor trafficking. Plasma membrane VEGFR interacting molecules, including vascular guidance receptors Neuropilins and Ephrins also regulate VEGFR endocytosis and trafficking. VEGF signaling is increasingly recognized for its roles outside of the vascular system, notably during neural development, and blood vessels regulate epithelial branching morphogenesis. We review here recent advances in our understanding of VEGF signaling and its biological roles. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Exercise training protects against atherosclerotic risk factors through vascular NADPH oxidase, extracellular signal-regulated kinase 1/2 and stress-activated protein kinase/c-Jun N-terminal kinase downregulation in obese rats.

    Science.gov (United States)

    Touati, Sabeur; Montezano, Augusto C I; Meziri, Fayçal; Riva, Catherine; Touyz, Rhian M; Laurant, Pascal

    2015-02-01

    Exercise training reverses atherosclerotic risk factors associated with metabolic syndrome and obesity. The aim of the present study was to determine the molecular anti-inflammatory, anti-oxidative and anti-atherogenic effects in aorta from rats with high-fat diet-induced obesity. Male Sprague-Dawley rats were placed on a high-fat (HFD) or control (CD) diet for 12 weeks. The HFD rats were then divided into four groups: (i) sedentary HFD-fed rats (HFD-S); (ii) exercise trained (motor treadmill 5 days/week, 60 min/day, 12 weeks) HFD-fed rats (HFD-Ex); (iii) modified diet (HFD to CD) sedentary rats (HF/CD-S); and (iv) an exercise-trained modified diet group (HF/CD-Ex). Tissue levels of NADPH oxidase (activity and expression), NADPH oxidase (Nox) 1, Nox2, Nox4, p47(phox) , superoxide dismutase (SOD)-1, angiotensin AT1 and AT2 receptors, phosphorylated mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)) and vascular cell adhesion molecule-1 (VCAM-1) were determined in the aorta. Plasma cytokines (tumour necrosis factor (TNF)-α and interleukin (IL)-6) levels were also measured. Obesity was accompanied by increases in NADPH oxidase activity, p47(phox) translocation, Nox4 and VCAM-1 protein expression, MAPK (ERK1/2, SAPK/JNK) phosphorylation and plasma TNF-α and IL-6 levels. Exercise training and switching from the HFD to CD reversed almost all these molecular changes. In addition, training increased aortic SOD-1 protein expression and decreased ERK1/2 phosphorylation. These findings suggest that protective effects of exercise training on atherosclerotic risk factors induced by obesity are associated with downregulation of NADPH oxidase, ERK1/2 and SAPK/JNK activity and increased SOD-1 expression. © 2014 Wiley Publishing Asia Pty Ltd.

  18. Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis.

    Science.gov (United States)

    Flore, R; Ponziani, F R; Di Rienzo, T A; Zocco, M A; Flex, A; Gerardino, L; Lupascu, A; Santoro, L; Santoliquido, A; Di Stasio, E; Chierici, E; Lanti, A; Tondi, P; Gasbarrini, A

    2013-09-01

    Vascular calcification and osteoporosis share similar etiopathogenetic mechanisms. Vitamin K2 deficiency could be responsible of the so called "calcium paradox", that is the lack of calcium in the bone and its storage in the vessel wall. These events may have clinically relevant consequences, such as cardiovascular accidents, and bone fractures. To review the biological function of vitamin K2 metabolism, the main factors related to its deficiency and the consequent clinical significance. Vitamin K2 is essential for the function of several proteins, involved in the maintenance of the normal structure of arterial wall, osteoarticular system, teeth, and for the regulation of cell growth. It has been demonstrated to have a pivotal role in the inhibition of vascular foci of calcification, and in the regulation of calcium deposition in the bone. Vitamin K2 deficiency is often subclinic in a large part of healthy population. This deficiency is related to the interaction of various factors, such as the reduced dietary intake, the alteration of intestinal absorption or production, with a possible role of intestinal microbiota and the increased consumption at the vessel wall. Vitamin K2 deficiency has recently been recognized as a protagonist in the development of vascular calcification and osteoporosis. Data reported so far are promising and, dietary supplementation seems a useful tool to contrast these diseases. However, large studies or solid clinical correlations regarding vitamin K2 deficiency and its pathologic consequences are needed to confirm these preliminary experiences.

  19. Uterine Vascular Lesions

    Science.gov (United States)

    Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

    2013-01-01

    Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID:24340126

  20. Magnetic resonance vascular imaging

    International Nuclear Information System (INIS)

    Axel, L

    1989-01-01

    The basis principles of MRI are reviewed in order to understand how blood flow effects arise in conventional imaging. Then some of the ways these effects have ben used in MRI techniques specifically designed for vascular imaging, are considered. (author)

  1. Arterial vascularization patterns of the splenium: An anatomical study.

    Science.gov (United States)

    Kahilogullari, G; Comert, A; Ozdemir, M; Brohi, R A; Ozgural, O; Esmer, A F; Egemen, N; Karahan, S T

    2013-09-01

    The aim of this study was to provide detailed information about the arterial vascularization of the splenium of the corpus callosum (CC). The splenium is unique in that it is part of the largest commissural tract in the brain and a region in which pathologies are seen frequently. An exact description of the arterial vascularization of this part of the CC remains under debate. Thirty adult human brains (60 hemispheres) were obtained from routine autopsies. Cerebral arteries were separately cannulated and injected with colored latex. Then, the brains were fixed in formaldehyde, and dissections were performed using a surgical microscope. The diameter of the arterial branches supplying the splenium of the CC at their origin was investigated, and the vascularization patterns of these branches were observed. Vascular supply to the splenium was provided by the anterior pericallosal artery (40%) from the anterior circulation and by the posterior pericallosal artery (88%) and posterior accessory pericallosal artery (50%) from the posterior circulation. The vascularization pattern of the splenium differs in each hemisphere and is usually supplied by multiple branches. The arterial vascularization of the splenium of the CC was studied comprehensively considering the ongoing debate and the inadequacy of the studies on this issue currently available in the literature. This anatomical knowledge is essential during the treatment of pathologies in this region and especially for splenial arteriovenous malformations.

  2. New options for vascularized bone reconstruction in the upper extremity.

    Science.gov (United States)

    Houdek, Matthew T; Wagner, Eric R; Wyles, Cody C; Nanos, George P; Moran, Steven L

    2015-02-01

    Originally described in the 1970s, vascularized bone grafting has become a critical component in the treatment of bony defects and non-unions. Although well established in the lower extremity, recent years have seen many novel techniques described to treat a variety of challenging upper extremity pathologies. Here the authors review the use of different techniques of vascularized bone grafts for the upper extremity bone pathologies. The vascularized fibula remains the gold standard for the treatment of large bone defects of the humerus and forearm, while also playing a role in carpal reconstruction; however, two other important options for larger defects include the vascularized scapula graft and the Capanna technique. Smaller upper extremity bone defects and non-unions can be treated with the medial femoral condyle (MFC) free flap or a vascularized rib transfer. In carpal non-unions, both pedicled distal radius flaps and free MFC flaps are viable options. Finally, in skeletally immature patients, vascularized fibular head epiphyseal transfer can provide growth potential in addition to skeletal reconstruction.

  3. Your Pathology Report

    Science.gov (United States)

    ... Pathology Tests Breast Cancer News February 20, 2013 Star-gazing software helps fight breast cancer See More ... Phone: (855) 807-6386 email Facebook Twitter Instagram YouTube Contact Us Privacy Policy Site Credits Terms of ...

  4. Stem Cell Pathology.

    Science.gov (United States)

    Fu, Dah-Jiun; Miller, Andrew D; Southard, Teresa L; Flesken-Nikitin, Andrea; Ellenson, Lora H; Nikitin, Alexander Yu

    2018-01-24

    Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.

  5. Pathology of pulmonary aspergillomas

    OpenAIRE

    Shah Rajeev; Vaideeswar Pradeep; Pandit Shobhana

    2008-01-01

    Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patien...

  6. Role of renal vascular potassium channels in physiology and pathophysiology

    DEFF Research Database (Denmark)

    Salomonsson, Max; Brasen, Jens Christian; Sorensen, Charlotte Mehlin

    2017-01-01

    The control of renal vascular tone is important for the regulation of salt and water balance, blood pressure and the protection against damaging elevated glomerular pressure. The K+ conductance is a major factor in the regulation of the membrane potential (Vm ) in vascular smooth muscle (VSMC...... the ambiguous in vitro and in vivo results. We discuss the role of single types of K+ channels and the integrated function of several classes. We also deal with the possible role of renal vascular K+ channels in the pathophysiology of hypertension, diabetes mellitus and sepsis. This article is protected...

  7. Retroperitoneoscopic nephrectomy in benign pathology.

    Science.gov (United States)

    Quintela, Rodrigo S; Cotta, Leonardo R; Neves, Marcelo F; Abelha, David L; Tavora, Jose E

    2006-01-01

    We report our experience with 43 retroperitoneal laparoscopic nephrectomy for benign kidney disease. All patients had a poor function from obstructive uropathology and renal atrophy. None of these patients had a previous lumbotomy. Retroperitoneoscopy was performed with 4 trocar port technique in a lateral position. The retroperitoneal space is created by using a Gaur's balloon made of sterile glove. The approach to vascular pedicle was done posteriorly and vessels were clipped by metal and Hem-o-lock (Weck Closure Systems, North Carolina, USA) clips. The sample was intact extracted in an Endo-Bag prolonging one trocar incision. Median operative time was 160 minutes and median blood loss was 200 mL. Four cases (9%) were converted to open surgery: one case due to bleeding and 3 cases due to technical difficulties regarding perirenal adherences. Most patients (39) checked out from the Hospital in day two. Four of them were left over 3 days due to wound complications. Retroperitoneoscopy offers a safe, effective and reproductive access to nephrectomy for benign pathologies.

  8. Seminal Fluid-Mediated Inflammation in Physiology and Pathology of the Female Reproductive Tract

    Directory of Open Access Journals (Sweden)

    Anthonio O. Adefuye

    2016-01-01

    Full Text Available Inflammation is a multifaceted process involving a host of resident and recruited immune cells that eliminate the insult or injury and initiate tissue repair. In the female reproductive tract (FMRT, inflammation-mediated alterations in epithelial, vascular, and immune functions are important components of complex physiological processes and many local and systemic pathologies. It is well established that intracoital and postcoital function of seminal fluid (SF goes beyond nutritive support for the spermatozoa cells. SF, in particular, the inflammatory bioactive lipids, and prostaglandins present in vast quantities in SF, have a role in localized immune modulation and regulation of pathways that can exacerbate inflammation in the FMRT. In sexually active women SF-mediated inflammation has been implicated in physiologic processes such as ovulation, implantation, and parturition while also enhancing tumorigenesis and susceptibility to infection. This review highlights the molecular mechanism by which SF regulates inflammatory pathways in the FMRT and how alterations in these pathways contribute to physiology and pathology of the female reproductive function. In addition, based on findings from TaqMan® 96-Well Plate Arrays, on neoplastic cervical cells treated with SF, we discuss new findings on the role of SF as a potent driver of inflammatory and tumorigenic pathways in the cervix.

  9. Gait and Equilibrium in Subcortical Vascular Dementia

    Directory of Open Access Journals (Sweden)

    Rita Moretti

    2011-01-01

    Full Text Available Subcortical vascular dementia is a clinical entity, widespread, even challenging to diagnose and correctly treat. Patients with this diagnosis are old, frail, often with concomitant pathologies, and therefore, with many drugs in therapy. We tried to diagnose and follow up for three years more than 600 patients. Study subjects were men and women, not bedridden, aged 68–94 years, outpatients, recruited from June, 1st 2007 to June, 1st 2010. We examined them clinically, neurologically, with specific consideration on drug therapies. Our aim has been to define gait and imbalance problem, if eventually coexistent with the pathology of white matter and/or with the worsening of the deterioration. Drug intake interference has been detected and considered.

  10. Laser therapy and sclerotherapy in the treatment of oral and maxillofacial hemangioma and vascular malformations

    Science.gov (United States)

    Crişan, Bogdan; BǎciuÅ£, Mihaela; BǎciuÅ£, Grigore; Crişan, Liana; Bran, Simion; Rotar, Horatiu; Moldovan, Iuliu; Vǎcǎraş, Sergiu; Mitre, Ileana; Barbur, Ioan; Magdaş, Andreea; Dinu, Cristian

    2016-03-01

    Hemangioma and vascular malformations in the field of oral and maxillofacial surgery is a pathology more often found in recent years in patients. The aim of this study was to evaluate the efficacy of the laser photocoagulation performed with a diode laser (Ga-Al-As) 980 nm wavelength in the treatment of vascular lesions which are located on the oral and maxillofacial areas, using color Doppler ultrasonography for evaluation of the results. We also made a comparison between laser therapy and sclerotherapy in order to establish treatment protocols and recommendations associated with this pathology. We conducted a controlled study on a group of 92 patients (38 male and 54 female patients, with an average age of 36 years) having low flow hemangioma and vascular malformations. Patients in this trial received one of the methods of treatment for vascular lesions such as hemangioma and vascular malformations: laser therapy or sclerotherapy. After laser therapy we have achieved a reduction in size of hemangioma and vascular malformations treated with such a procedure, and the aesthetic results were favorable. No reperfusion or recanalization of laser treated vascular lesions was observed after an average follow-up of 6 to 12 months. In case of sclerotherapy a reduction in the size of vascular lesions was also obtained. The 980 nm diode laser has been proved to be an effective tool in the treatment of hemangioma and vascular malformations in oral and maxillofacial area. Laser therapy in the treatment of vascular lesions was more effective than the sclerotherapy procedure.

  11. Imaging of Cerebrovascular Pathology in Animal Models of Alzheimer`s Disease

    Directory of Open Access Journals (Sweden)

    Jan eKlohs

    2014-03-01

    Full Text Available In Alzheimer’s disease (AD, vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature.

  12. Sirtuins, Cell Senescence, and Vascular Aging.

    Science.gov (United States)

    Kida, Yujiro; Goligorsky, Michael S

    2016-05-01

    The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  13. Effects of PPARγ ligands on vascular tone.

    Science.gov (United States)

    Salomone, Salvatore; Drago, Filippo

    2012-06-01

    Peroxisome Proliferator-Activated Receptor γ (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind and activate both PPARγ and PPARα), and other experimental drugs (still in development) that exploit the chemistry of thiazolidinediones as a scaffold for PPARγ-independent pharmacological properties. In this review, we examine both short (mostly from in vitro data)- and long (mostly from in vivo data)-term effects of PPARγ ligands that extend from PPARγ-independent vascular effects to PPARγ-dependent gene expression. Because endothelium is a master regulator of vascular tone, we have attempted to differentiate between endothelium-dependent and endothelium-independent effects of PPARγ ligands. Based on available data, we conclude that PPARγ ligands appear to influence vascular tone in different experimental paradigms, most often in terms of vasodilatation (potentially increasing blood flow to some tissues). These effects on vascular tone, although potentially beneficial, must be weighed against specific cardiovascular warnings that may apply to some drugs, such as rosiglitazone.

  14. [Adolescent pathological gambling].

    Science.gov (United States)

    Petit, A; Karila, L; Lejoyeux, M

    2015-05-01

    Although experts have long thought that the problems of gambling involved only adults, recent studies tend to show that teenagers are also affected. The objective of this paper is to show the characteristics of pathological gambling in adolescents. This review focuses on the clinical features, prevalence, psychopathology, prevention and treatment of this disorder. A review of the medical literature was conducted, using PubMed, using the following keywords alone or combined: pathological gambling, dependence, addiction and adolescents. We selected 12 English articles from 1997 to 2014. Recent work estimate that between 4 and 8% of adolescents suffer from problem gambling, and the prevalence of pathological gambling is 2-4 times higher in adolescents than in adults. The term adolescent pathological gambler starts early around the age of 10-12 years, with a quick change of status from casual to that of problem gambler and player. Complications appear quickly and comorbidities are common. There is no curative pharmacological treatment approved by health authorities. Pathological gambling among adolescents has grown significantly in recent years and should be promptly taken care of. Further studies must be performed to improve our understanding of this problem among adolescents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. Pathologic conditions in pregnancy

    International Nuclear Information System (INIS)

    Beomonte Zobel, B.; Tella, S.; Innacoli, M.; D'Archivio, C.; Cardone, G.; Masciocchi, C.; Gallucci, M.; Passariello, R.; Cappa, F.

    1991-01-01

    Soma authors suggested that MR imaging could rapresent an effective diagnostic alternative in the study of pathologic conditions of mother and fetus during pregnancy. To verify the actual role of MR imaging, we examined 20 patients in the 2nd and 3rd trimester of gestation, after a preliminary US examination. Fifteen patients presented fetal or placental pathologies; in 4 patients the onset of the pathologic condition occurred during pregnancy; in 1 case of US diagnosis of fetal ascites, MR findings were nornal and the newborn was healty. As for placental pathologies, our series included a case of placental cyst, two hematomas between placenta and uterine wall, and two cases of partial placenta previa. As for fetal malformation, we evaluated a case of omphalocele, one of Prune-Belly syndrome, a case of femoral asimmetry, one of thanatophoric dwarfism, a case of thoracopagus twins with cardiovascular abnormalities, two fetal hydrocephali, and three cases of pyelo-ureteral stenosis. As for maternal pathologies during pregnancy, we observed a case of subserous uterine fibromyoma, one of of right hydronephrosis, one of protrusion of lumbar invertebral disk, and a large ovarian cyst. In our experience, MR imaging exhibited high sensitivity and a large field of view, which were both useful in the investigation of the different conditions occurring during pregnancy. In the evaluation of fetal and placental abnormalities, especially during the 3rd trimester, the diagnostic yieldof MR imaging suggested it as a complementary technique to US for the evaluation of fetal malformation and of intrauterine growth retardation

  16. The making of indigenous vascular prosthesis

    Directory of Open Access Journals (Sweden)

    Madathipat Unnikrishnan

    2016-01-01

    Full Text Available Background & objectives: Vascular illnesses are on the rise in India, due to increase in lifestyle diseases and demographic transition, requiring intervention to save life, organ or limbs using vascular prosthesis. The aim of this study was to develop indigenous large diameter vascular graft for treatment of patients with vascular pathologies. Methods: The South India Textile Research Association, at Coimbatore, Tamil Nadu, India, developed seamless woven polyester (Polyethylene terephthalate graft at its research wing. Further characterization and testing followed by clinical trials were conducted at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India. Fifteen in vivo experiments were carried out in 1992-1994 in pigs as animal model. Controlled (phase I clinical trial in ten patients was performed along with control graft. Thereafter, phase II trial involved 22 patients who underwent multi-centre clinical trial in four centres across India. Results: Laboratory testing showed that polyester graft was non-toxic, non-leeching and non-haemolytic with preserved long-term quality, further confirming in pigs by implanting in thoracic aorta, comparable to control Dacron grafts. Perigraft incorporation and smooth neointima formation which are prime features of excellent healing characteristics, were noted at explantation at planned intervals. Subsequently in the phase I and II clinical trials, all patients had excellent recovery without mortality or device-related adverse events. Patients receiving the test graft were followed up for 10 and 5 years, respectively. Serial clinical, duplex scans and CT angiograms performed periodically confirmed excellent graft performance. Interpretation & conclusions: Indigenously developed Chitra vascular graft was comparable to commercially available Dacron graft, ready for clinical use at affordable cost to patients as against costly imported grafts.

  17. Overview of vascular disease

    International Nuclear Information System (INIS)

    Bisset, G.S. III

    1998-01-01

    Vascular disease in the pediatric population is a poorly understood process which is often underestimated in its incidence. The common beginnings of such ubiquitous diseases as atherosclerosis manifest themselves at a cellular level shortly after birth. Other common systemic disorders, including congestive heart failure and sepsis, are also intricately associated with dysfunctional vasculature. Progress in the understanding of normal and pathophysiologic processes within the vascular system begins with the 'control center' - the endothelial cell. The purpose of this review is to consolidate a body of knowledge on the processes that occur at the cellular level within the blood vessel wall, and to simplify the understanding of how imbalances in these physiologic parameters result in vascular disease. (orig.)

  18. Pathological review of late cerebral radionecrosis

    International Nuclear Information System (INIS)

    Yoshii, Yoshihiko

    2008-01-01

    Late cerebral radionecrosis may be considered to be a specific chronic inflammatory response, although it is unknown whether the initial damage by brain irradiation is to an endothelial cell or a glial cell. I discuss the pathological specificity of late cerebral radionecrosis by studying the published literature and a case that I experienced. In late cerebral radionecrosis, there are typical coagulation necrosis areas containing fibrinoid necrosis with occlusion of the lumina and poorly active inflammatory areas with many inflammatory ghost cells, focal perivascular lymphocytes, hyalinized vessels, and telangiectatic vascularization near and in the necrotic tissue, and more active inflammatory areas formed as a partial rim of the reactive zone by perivascular lymphocytes, much vascularization, and glial fibrillary acidic protein (GFAP)-positive astrocytes at the corticomedullary border adjacent to necrotic tissue in the white matter. It is difficult to believe that coagulation necrosis occurs without first disordering the vascular endothelial cells because fibrinoid necrosis is a main feature and a diffusely multiple lesion in late cerebral radionecrosis. Because various histological findings do develop, progress, and extend sporadically at different areas and times in the irradiated field of the brain for a long time after radiation, uncontrolled chronic inflammation containing various cytokine secretions may also play a key role in progression of this radionecrosis. Evaluation of the mechanism of the development/aggravation of late cerebral radionecrosis requires a further study for abnormal cytokine secretions and aberrant inflammatory reactions. (author)

  19. Audit in forensic pathology.

    Science.gov (United States)

    Burke, M P; Opeskin, K

    2000-09-01

    Autopsy numbers in Australian hospitals have declined markedly during the past decade despite evidence of a relatively static rate of demonstrable clinical misdiagnosis during this time. The reason for this decrease in autopsy numbers is multifactorial and may include a general lack of clinical and pathologic interest in the autopsy with a possible decline in autopsy standard, a lack of clinicopathologic correlation after autopsies, and an increased emphasis on surgical biopsy reporting within hospital pathology departments. Although forensic autopsies are currently maintaining their numbers, it is incumbent on forensic pathologists to demonstrate the wealth of important information a carefully performed postmortem examination can reveal. To this end, the Pathology Division of the Victorian Institute of Forensic Medicine has instituted a program of minimum standards in varied types of coroner cases and commenced a system of internal and external audit. The minimum standard for a routine, sudden, presumed natural death is presented and the audit system is discussed.

  20. Dual Pathology of Mandible.

    Science.gov (United States)

    Rajurkar, Suday G; Deshpande, Mohan D; Kazi, Noaman; Jadhav, Dhanashree; Ranadive, Pallavi; Ingole, Snehal

    2017-01-01

    Aneurysmal Bone cyst (ABC)is a rare benign lesion of the bone which is infrequent in craniofacial region (12%). Rapid growth pattern causing bone expansion and facial asymmetry is a characteristic feature of ABC. Giant cell lesion is another distinct pathological entity. Here we present to you a rare case of dual pathology in an 11 year old female patient who presented with a large expansile lesion in the left hemimandible. All radiographic investigations were suggestive of ABC, aspiration of the lesion resulted in blood aspirate. However only after a histologic examination the dual nature of the lesion was revealed.

  1. Hip joint pathology

    DEFF Research Database (Denmark)

    Tijssen, M; van Cingel, R E H; de Visser, E

    2017-01-01

    The purpose of this retrospective cohort study was to (a) describe the clinical presentation of femoroacetabular impingement (FAI) and hip labral pathology; (b) describe the accuracy of patient history and physical tests for FAI and labral pathology as confirmed by hip arthroscopy. Patients (18......-65 years) were included if they were referred to a physical therapist to gather pre-operative data and were then diagnosed during arthroscopy. Results of pre-operative patient history and physical tests were collected and compared to arthroscopy. Data of 77 active patients (mean age: 37 years) were...

  2. Vascular targeting with peptide libraries

    Energy Technology Data Exchange (ETDEWEB)

    Pasqualini, R. [La Jolla Cancer Research Center The Burnham Inst., La Jolla CA (United States)

    1999-06-01

    The authors have developed an 'in vivo' selection system in which phage capable of selective homing to different tissues are recovered from a phage display peptide library following intravenous administration. Using this strategy, they have isolate several organ and tumor-homing peptides. They have shown that each of those peptides binds of different receptors that are selectively expressed on the vasculature of the target tissue. The tumor-homing peptides bind to receptors that are up regulated in tumor angiogenic vasculature. Targeted delivery of doxorubicin to angiogenic vasculature using these peptides in animals models decrease toxicity and increased the therapeutic efficacy of the drug. Vascular targeting may facilitate the development of other treatment strategies that rely on inhibition of angio genesis and lead to advances to extend the potential for targeting of drugs, genes and radionuclides in the context of many diseases.

  3. Ethics and Professionalism in Pathology

    Directory of Open Access Journals (Sweden)

    R Baral

    2016-03-01

    Full Text Available Pathologists spend most of their professional lives beyond direct view of the public, mostly inside the four walls of the lab. It is the clinicians who face the wrath of the public when something goes wrong. However, with the growing awareness of the public into the decisive role played by the Pathologists in the definitive diagnosis of the disease, the pathologists will soon be the target of the aggrieved patients and relatives.1 The issue of ethics can be dealt when professionalism comes before profession. "Professionalism in medicine requires that physician serve the interests of the patient above his or her own selfinterest." Professionalism aspires to philanthropy, answerability, excellence, duty, service and respect for others. "Professionalism in Pathology is based on the same tenets, but has additional dimensions."The qualities of professionalism for pathologists include 1. Communication with the patients and the clinicians. A small phone call with the clinician will solve most of the clinical mysteries not written in the lab requisition forms; 2. Empathy and Compassion towards patients', colleagues', and laboratory personnel's culture, age, gender, and disabilities; 3. Demonstration of passion, respect and understanding towards the patients; 4. Adherence to guidelines and regulations of the regulatory and accrediting bodies; and 5.Profeciency and knowledge in one's work is valued by the patients more than the credentials, which also enables one to identify deficiencies in peer performance. The basic competencies of professionalism are vital to every pathology report, which in turn is the mirror of the ethics practiced by the pathologist. Evaluating oneself is perhaps the most important tool in maintaining professionalism in the practice of pathology. One colleague recently defined professionalism as “all the things one does when no one is watching,” thus placing personal integrity at the top of the list.

  4. Accelerated Vascular Aging as a Paradigm for Hypertensive Vascular Disease: Prevention and Therapy.

    Science.gov (United States)

    Barton, Matthias; Husmann, Marc; Meyer, Matthias R

    2016-05-01

    Aging is considered the most important nonmodifiable risk factor for cardiovascular disease and death after age 28 years. Because of demographic changes the world population is expected to increase to 9 billion by the year 2050 and up to 12 billion by 2100, with several-fold increases among those 65 years of age and older. Healthy aging and prevention of aging-related diseases and associated health costs have become part of political agendas of governments around the world. Atherosclerotic vascular burden increases with age; accordingly, patients with progeria (premature aging) syndromes die from myocardial infarctions or stroke as teenagers or young adults. The incidence and prevalence of arterial hypertension also increases with age. Arterial hypertension-like diabetes and chronic renal failure-shares numerous pathologies and underlying mechanisms with the vascular aging process. In this article, we review how arterial hypertension resembles premature vascular aging, including the mechanisms by which arterial hypertension (as well as other risk factors such as diabetes mellitus, dyslipidemia, or chronic renal failure) accelerates the vascular aging process. We will also address the importance of cardiovascular risk factor control-including antihypertensive therapy-as a powerful intervention to interfere with premature vascular aging to reduce the age-associated prevalence of diseases such as myocardial infarction, heart failure, hypertensive nephropathy, and vascular dementia due to cerebrovascular disease. Finally, we will discuss the implementation of endothelial therapy, which aims at active patient participation to improve primary and secondary prevention of cardiovascular disease. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  5. Pathological Gambling Subtypes

    Science.gov (United States)

    Vachon, David D.; Bagby, R. Michael

    2009-01-01

    Although pathological gambling (PG) is regarded in the 4th edition of the "Diagnostic and Statistical Manual of Mental Disorders" (American Psychiatric Association, 1994) as a unitary diagnostic construct, it is likely composed of distinct subtypes. In the current report, the authors used cluster analyses of personality traits with a…

  6. TC pathological Neck

    International Nuclear Information System (INIS)

    Garcia Fontes, M.

    2012-01-01

    This presentation is about different imaging techniques such as ultrasound, CT, RNM, PET-CT. These techniques permit to detect head and neck tumors, breast and digestive pathologies as well as congenital diseases and glandular tumor in the thyroid, parathyroid, muscles, lymphatic, nerves and vessels

  7. Pathological fractures in children

    Science.gov (United States)

    De Mattos, C. B. R.; Binitie, O.; Dormans, J. P.

    2012-01-01

    Pathological fractures in children can occur as a result of a variety of conditions, ranging from metabolic diseases and infection to tumours. Fractures through benign and malignant bone tumours should be recognised and managed appropriately by the treating orthopaedic surgeon. The most common benign bone tumours that cause pathological fractures in children are unicameral bone cysts, aneurysmal bone cysts, non-ossifying fibromas and fibrous dysplasia. Although pathological fractures through a primary bone malignancy are rare, these should be recognised quickly in order to achieve better outcomes. A thorough history, physical examination and review of plain radiographs are crucial to determine the cause and guide treatment. In most benign cases the fracture will heal and the lesion can be addressed at the time of the fracture, or after the fracture is healed. A step-wise and multidisciplinary approach is necessary in caring for paediatric patients with malignancies. Pathological fractures do not have to be treated by amputation; these fractures can heal and limb salvage can be performed when indicated. PMID:23610658

  8. Next-Generation Pathology.

    Science.gov (United States)

    Caie, Peter D; Harrison, David J

    2016-01-01

    The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

  9. Forms of pathologization

    DEFF Research Database (Denmark)

    Brinkmann, Svend

    disorder, and similar figures are found for many other mental disorders. These figures are striking, but are hard to interpret. This presentation argues in favour of the pathologization thesis, which claims that it cannot be argued in a straightforward manner that we are simply more ill and disordered than...

  10. Renal posttransplant's vascular complications

    Directory of Open Access Journals (Sweden)

    Bašić Dragoslav

    2003-01-01

    Full Text Available INTRODUCTION Despite high graft and recipient survival figures worldwide today, a variety of technical complications can threaten the transplant in the postoperative period. Vascular complications are commonly related to technical problems in establishing vascular continuity or to damage that occurs during donor nephrectomy or preservation [13]. AIM The aim of the presenting study is to evaluate counts and rates of vascular complications after renal transplantation and to compare the outcome by donor type. MATERIAL AND METHODS A total of 463 kidneys (319 from living related donor LD and 144 from cadaveric donor - CD were transplanted during the period between June 1975 and December 1998 at the Urology & Nephrology Institute of Clinical Centre of Serbia in Belgrade. Average recipients' age was 33.7 years (15-54 in LD group and 39.8 (19-62 in CD group. Retrospectively, we analyzed medical records of all recipients. Statistical analysis is estimated using Hi-squared test and Fischer's test of exact probability. RESULTS Major vascular complications including vascular anastomosis thrombosis, internal iliac artery stenosis, internal iliac artery rupture obliterant vasculitis and external iliac vein rupture were analyzed. In 25 recipients (5.4% some of major vascular complications were detected. Among these cases, 22 of them were from CD group vs. three from LD group. Relative rate of these complications was higher in CD group vs. LD group (p<0.0001. Among these complications dominant one was vascular anastomosis thrombosis which occurred in 18 recipients (17 from CD vs. one from LD. Of these recipients 16 from CD lost the graft, while the rest of two (one from each group had lethal outcome. DISCUSSION Thrombosis of renal allograft vascular anastomosis site is the most severe complication following renal transplantation. In the literature, renal allograft thrombosis is reported with different incidence rates, from 0.5-4% [14, 15, 16]. Data from the

  11. FGF-dependent metabolic control of vascular development

    Science.gov (United States)

    Yu, Pengchun; Alves, Tiago C.; Fang, Jennifer S.; Xie, Yi; Zhu, Jie; Chen, Zehua; De Smet, Frederik; Zhang, Jiasheng; Jin, Suk-Won; Sun, Lele; Sun, Hongye; Kibbey, Richard G.; Hirschi, Karen K.; Hay, Nissim; Carmeliet, Peter; Chittenden, Thomas W.; Eichmann, Anne; Potente, Michael; Simons, Michael

    2017-01-01

    Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are of importance to these processes1. While much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism2,3, little is understood about the role of fibroblast growth factors (FGFs) in this context4. Here we identify FGF receptor (FGFR) signaling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signaling inputs results in decreased glycolysis leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/r3 double mutant mice while HK2 overexpression partially rescues the defects caused by suppression of FGF signaling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development. PMID:28467822

  12. [Vascular depression in the elderly. Does inflammation play a role?].

    Science.gov (United States)

    Viscogliosi, Giovanni; Andreozzi, Paola; Chiriac, Iulia Maria; Ettorre, Evaristo; Vulcano, Achiropita; Servello, Adriana; Marigliano, Benedetta; Marigliano, Vincenzo

    2011-06-01

    Vascular depression in the elderly. Does inflammation play a role?Depression is the most common comorbidity in the elderly, and it is a major determinant of disability. The late-onset depression in highly associated to cardiovascular disease. Depressive symptoms may follow vascular brain damage, especially when mood regulating areas are affected. However depression is strongly associated to vascular disease even when there is no manifest brain damage. Recently great attention has been given to chronic inflammation, both related to depression and vascular disease. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids in depressed patients is associated with defect in serotonergic function. Chronic inflammation may underlie many forms of depression associated with vascular disease and metabolic syndrome. The importance of the inflammation hypothesis of depression lies is that psychotropic drugs may have central anti-inflammatory action, and that new generation of central anti-inflammatory drugs may be useful in depression treatment.

  13. New aspects of vascular remodelling: the involvement of all vascular cell types.

    Science.gov (United States)

    McGrath, John C; Deighan, Clare; Briones, Ana M; Shafaroudi, Majid Malekzadeh; McBride, Melissa; Adler, Jeremy; Arribas, Silvia M; Vila, Elisabet; Daly, Craig J

    2005-07-01

    Conventionally, the architecture of arteries is based around the close-packed smooth muscle cells and extracellular matrix. However, the adventitia and endothelium are now viewed as key players in vascular growth and repair. A new dynamic picture has emerged of blood vessels in a constant state of self-maintenance. Recent work raises fundamental questions about the cellular heterogeneity of arteries and the time course and triggering of normal and pathological remodelling. A common denominator emerging in hypertensive remodelling is an early increase in adventitial cell density suggesting that adventitial cells drive remodelling and may initiate subsequent changes such as re-arrangement of smooth muscle cells and extracellular matrix. The organization of vascular smooth muscle cells follows regular arrangements that can be modelled mathematically. In hypertension, new patterns can be quantified in these terms and give insights to how structure affects function. As with smooth muscle, little is known about the organization of the vascular endothelium, or its role in vascular remodelling. Current observations suggest that there may be a close relationship between the helical organization of smooth muscle cells and the underlying pattern of endothelial cells. The function of myoendothelial connections is a topic of great current interest and may relate to the structure of the internal elastic lamina through which the connections must pass. In hypertensive remodelling this must present an organizational challenge. The objective of this paper is to show how the functions of blood vessels depend on their architecture and a continuous interaction of different cell types and extracellular proteins.

  14. XXXI LIAC Meeting on Vascular Research - Proceedings

    Directory of Open Access Journals (Sweden)

    L. Monteiro Rodrigues et al.

    2015-12-01

    ência Keynote Speaker | Prelector Livia Visai Free Comunications | Comunicações livres Speakers | Prelectores Gabriele Corsaro Michel Spina Ricardo Moreira Keynote lecture 5 | 5ª Conferência Keynote Speaker | Prelector Antonio D'Amore 4st Session |Sessão 4 Innovation and Technology from Diagnostics to Therapeutics | Inovação e Tecnologia de Diagnóstico à Terapêutica Charmain | Moderador - Philippe Charpiot Keynote lecture 6 | 6ª Conferência Keynote Speaker | Prelector Laurent Riou Free Comunications | Comunicações livres Speakers | Prelectores Carlota Saldanha Eduardo Vilela Hugo Ferreira Keynote lecture 7 | 7ª Conferência Keynote Speaker | Prelecto Geoffrey Mitchell 12 September | 12 de Setembro 5st Session |Sessão 4 Clinical Applications | Aplicações Clínicas Charmain | Moderador - Vicenta Llorente-Cortés Free Comunications | Comunicações livres Speakers | Prelectores Antonio Leppeda Henrique Silva Diogo Fonseca Open Session ANTONIO TAMBURRO Conference 1st Session | Sessão 1 Molecular and Supramolecular Structure | Estrutura Molecular e Supramolecular Chairman / Moderador Alain Pierre Gadeau C.01 - Molecular and Supramolecular Structure of glycopeptides as scaffolds in tissue engineering (U Basilicata Speaker / Prelector Brigida Bochicchio C.02 - Domain CR9 of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1 Is Critical for Aggregated LDL-Induced Foam Cell Formation from Human Vascular Smooth Muscle Cells (CSIC-ICCC, Barcelona Speaker / Prelector Vicenta Llorente-Cortés 1st Session | Sessão 1 Molecular and Supramolecular Structure | Estrutura Molecular e Supramolecular C.03 - Beneficial effects of physical training on the vascular dysfunction induced by intermittent hypoxia (U Grenoble - U Libanaise Speaker / Prelector Zeinab El Dirani C.04 - Protocols for studying Pelvic Venous Pathology (Hospital Rúber Internacional, Madrid Speaker / Prelector Leal Monedero 1st Session | Sessão 1 Molecular and Supramolecular Structure | Estrutura

  15. Bone Marrow Vascular Niche: Home for Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Ningning He

    2014-01-01

    Full Text Available Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs. As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.

  16. Pathology informatics fellowship training: Focus on molecular pathology

    Directory of Open Access Journals (Sweden)

    Diana Mandelker

    2014-01-01

    Full Text Available Background: Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Methods and Results: Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program′s core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. Conclusions: The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

  17. Pathology informatics fellowship training: Focus on molecular pathology.

    Science.gov (United States)

    Mandelker, Diana; Lee, Roy E; Platt, Mia Y; Riedlinger, Gregory; Quinn, Andrew; Rao, Luigi K F; Klepeis, Veronica E; Mahowald, Michael; Lane, William J; Beckwith, Bruce A; Baron, Jason M; McClintock, David S; Kuo, Frank C; Lebo, Matthew S; Gilbertson, John R

    2014-01-01

    Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program's core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

  18. Major Vascular Neurocognitive Disorder: A Reappraisal to Vascular Dementia

    Directory of Open Access Journals (Sweden)

    Emre Kumral

    2017-03-01

    Full Text Available Major vascular neurocognitive disorder (NCD is the second leading form of dementia after Alzheimer’s disease, accounting for 17-20% of all dementias. Vascular NCD is a progressive disease caused by reduced cerebral blood flow related to multiple large volume or lacunar infarcts that induce a sudden onset and stepwise decline in cognitive abilities. Despite its prevalence and clinical importance, there is still controversy in the terminology of vascular NCD. Only after the release of Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5 (2013 did the American Psychiatric Association define vascular dementia as “major vascular NCD”. This review includes an overview of risk factors, pathophysiology, types, diagnostic and clinical features of major vascular NCD, and current treatment options of vascular NCD regarding to DSM-5 criteria

  19. Heme oxygenase and the immune system in normal and pathological pregnancies

    Directory of Open Access Journals (Sweden)

    Maide eOzen

    2015-04-01

    Full Text Available Normal pregnancy is an immunotolerant state. Many factors, including environmental, socioeconomic, genetic, and immunologic changes by infection and/or other causes of inflammation, may contribute to inter-individual differences resulting in a normal or pathologic pregnancy. In particular, imbalances in the immune system can cause many pregnancy-related diseases, such as infertility, abortions, pre-eclampsia, and preterm labor, which result in maternal/fetal death, prematurity, or small-for-gestational age newborns. New findings imply that myeloid regulatory cells and regulatory T cells (Tregs may mediate immunotolerance during normal pregnancy. Effector T cells (Teffs have, in contrast, been implicated to cause adverse pregnancy outcomes. Furthermore, feto-maternal tolerance affects the developing fetus. It has been shown that the Treg/Teff balance affects litter size and adoptive transfer of pregnancy-induced Tregs can prevent fetal rejection in the mouse. Heme oxygenase-1 (HO-1 has a protective role in many conditions through its anti-inflammatory, anti-apoptotic, antioxidative, and anti-proliferative actions. HO-1 is highly expressed in the placenta and plays a role in angiogenesis and placental vascular development and in regulating vascular tone in pregnancy. In addition, HO-1 is a major regulator of immune homeostasis by mediating crosstalk between innate and adaptive immune systems. Moreover, HO-1 can inhibit inflammation-induced phenotypic maturation of immune effector cells and pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine production. HO-1 may also be associated with T-cell activation and can limit immune-based tissue injury by promoting Treg suppression of effector responses. Thus, HO-1 and its byproducts may protect against pregnancy complications by its immunomodulatory effects, and the regulation of HO-1 or its downstream effects has the potential to prevent or treat pregnancy complications and

  20. Male breast pathology

    International Nuclear Information System (INIS)

    Puebla, C.; Sainz, J.M.; Pujala, M.; Villavieja, J.L.

    1998-01-01

    To review the specific radiological signs of male breast pathology observed in our center over the past five years, as well as the pertinent medical literature. A retrospective study was carried out of the 47 mammographic studies performed in 41 men. Oblique mediolateral and craniocaudal views were employed. The distribution of different types of male breast pathology among our patients was as follows: gynecomastia was detected in 30 cases (73.1%), pseudogynectomastia in 4 (9.7%), carcinoma in 3(7.3%), abscess in 2 (4.9%), lipoma in 1 (2.5%) and epidermoid cyst in the remaining patient (2.5%). The results obtained agree with those reported in the literature reviewed. The most significant findings were the low incidence of carcinoma and the high rate of gynecomastia. (Author) 26 refs

  1. Pathology of pulmonary aspergillomas.

    Science.gov (United States)

    Shah, Rajeev; Vaideeswar, Pradeep; Pandit, Shobhana P

    2008-01-01

    Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patients were in their fourth decade. Episodic hemoptysis was the commonest mode of presentation (85.4%). Forty aspergillomas were complex, occurring in cavitatory lesions (82.9%) or in bronchiectasis (14.6%). Simple aspergilloma was seen as an incidental finding in only one. Tuberculosis was the etiological factor in 31 patients, producing cavitatory or bronchiectatic lesions; other causes were chronic lung abscess and bronchiectasis (unrelated to tuberculosis). Surgical resections are endorsed in view of high risk of unpredictable, life-threatening hemoptysis.

  2. Pathology of pulmonary aspergillomas

    Directory of Open Access Journals (Sweden)

    Shah Rajeev

    2008-07-01

    Full Text Available Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patients were in their fourth decade. Episodic hemoptysis was the commonest mode of presentation (85.4%. Forty aspergillomas were complex, occurring in cavitatory lesions (82.9% or in bronchiectasis (14.6%. Simple aspergilloma was seen as an incidental finding in only one. Tuberculosis was the etiological factor in 31 patients, producing cavitatory or bronchiectatic lesions; other causes were chronic lung abscess and bronchiectasis (unrelated to tuberculosis. Surgical resections are endorsed in view of high risk of unpredictable, life-threatening hemoptysis.

  3. [Pathological gambling: risk factors].

    Science.gov (United States)

    Bouju, G; Grall-Bronnec, M; Landreat-Guillou, M; Venisse, J-L

    2011-09-01

    In France, consumption of gambling games increased by 148% between 1960 and 2005. In 2004, gamblers lost approximately 0.9% of household income, compared to 0.4% in 1960. This represents approximately 134 Euros per year and per head. In spite of this important increase, the level remains lower than the European average (1%). However, gambling practices may continue to escalate in France in the next few years, particularly with the recent announce of the legalisation of online games and sports betting. With the spread of legalised gambling, pathological gambling rates may increase in France in the next years, in response to more widely available and more attractive gambling opportunities. In this context, there is a need for better understanding of the risk factors that are implicated in the development and maintenance of pathological gambling. This paper briefly describes the major risk factors for pathological gambling by examining the recent published literature available during the first quarter of 2008. This documentary basis was collected by Inserm for the collective expert report procedure on Gambling (contexts and addictions). Seventy-two articles focusing on risk factors for pathological gambling were considered in this review. Only 47 of them were taken into account for analysis. The selection of these 47 publications was based on the guide on literature analysis established by the French National Agency for Accreditation and Assessment in Health (ANAES, 2000). Some publications from more recent literature have also been added, mostly about Internet gambling. We identify three major types of risk factors implicated in gambling problems: some of them are related to the subject (individual factors), others are related to the object of the addiction, here the gambling activity by itself (structural factors), and the last are related to environment (contextual or situational factors). Thus, the development and maintenance of pathological gambling seems to be

  4. Update on vascular endothelial Ca(2+) signalling: A tale of ion channels, pumps and transporters.

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-07-26

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca(2+) signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca(2+) levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca(2+) signals, ranging from brief, localized Ca(2+) pulses to prolonged Ca(2+) oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca(2+) signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca(2+) releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca(2+) removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca(2+) machinery in vascular ECs under both physiological and pathological conditions.

  5. Update on vascular endothelial Ca2+ signalling: A tale of ion channels, pumps and transporters

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-01-01

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca2+ signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca2+ levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca2+ signals, ranging from brief, localized Ca2+ pulses to prolonged Ca2+ oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca2+ signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca2+ releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca2+ removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca2+ machinery in vascular ECs under both physiological and pathological conditions. PMID:22905291

  6. Plant Vascular Biology 2010

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Biao

    2014-11-17

    This grant supported the Second International Conference on Plant Vascular Biology (PVB 2010) held July 24-28, 2010 on the campus of Ohio State University, Columbus, Ohio. Biao Ding (Ohio State University; OSU) and David Hannapel (Iowa State University; ISU) served as co-chairs of this conference. Biao Ding served as the local organizer. PVB is defined broadly here to include studies on the biogenesis, structure and function of transport systems in plants, under conditions of normal plant growth and development as well as of plant interactions with pathogens. The transport systems cover broadly the xylem, phloem, plasmodesmata and vascular cell membranes. The PVB concept has emerged in recent years to emphasize the integrative nature of the transport systems and approaches to investigate them.

  7. Vascular Surgery and Robotics

    Directory of Open Access Journals (Sweden)

    Indrani Sen

    2016-01-01

    Full Text Available The application of robotics to Vascular surgery has not progressed as rapidly as of endovascular technology, but this is changing with the amalgamation of these two fields. The advent of Endovascular robotics is an exciting field which overcomes many of the limitations of endovascular therapy like vessel tortuosity and operator fatigue. This has much clinical appeal for the surgeon and hold significant promise of better patient outcomes. As with most newer technological advances, it is still limited by cost and availability. However, this field has seen some rapid progress in the last decade with the technology moving into the clinical realm. This review details the development of robotics, applications, outcomes, advantages, disadvantages and current advances focussing on Vascular and Endovascular robotics

  8. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

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    Raymond Y. Lo

    2015-02-01

    Full Text Available Background: The contributions of vascular risk factors to spinocerebellar ataxia (SCA are not known.Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account.Results: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion: Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.

  9. Pathologic correlation to internal echogenicity of atypical breast fibroadenoma

    International Nuclear Information System (INIS)

    Cho, Nariya; Oh, Ki Keun; Kwon, Ryang; Han, Jae Ho; Jung, Woo Hee; Lee, Hy De

    1998-01-01

    To understand the cause of a typical sonographic findings by analyzing their pathologic correlation to internal echogenicity of breast fibroadenoma. Materials and Methods : Between January 1995 and April 1997, the presence of 91 fibroadenomas in 81 patients was histopathologically proven. These mass lesions were sonographically interpreted and their descriptive criteria-internal echo content (both strength and homogeneity),the presence of septum, bilateral shadowing, and posterior echo pattern-were tabulated. A pathologist reviewed each case and independently recorded the following data : cell type, the presence of septum, duct dilatation,calcification, fibrosis, hyalinization, and vascularity. We analyzed the correlation of sonographic with pathologic findings. Results : There was significant correlation between increased vascularity and increased internal echo strength and between increased fibrosis and decreased internal echo strength. There was no significant correlation between internal echo homogeneity or posterior shadowing and vascularity or stromal fibrosis, nor between hyalinization or cell type and internal echo strength, homogeneity or posterior shadowing.There was correlation between absent or thin capsule and the absence of bilateral shadowing. Conclusion :Increased vascularity or decreased stromal fibrosis might be the cause of atypical fibroadenoma

  10. Pathologic correlation to internal echogenicity of atypical breast fibroadenoma

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Nariya; Oh, Ki Keun; Kwon, Ryang; Han, Jae Ho; Jung, Woo Hee; Lee, Hy De [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

    1998-07-01

    To understand the cause of a typical sonographic findings by analyzing their pathologic correlation to internal echogenicity of breast fibroadenoma. Materials and Methods : Between January 1995 and April 1997, the presence of 91 fibroadenomas in 81 patients was histopathologically proven. These mass lesions were sonographically interpreted and their descriptive criteria-internal echo content (both strength and homogeneity),the presence of septum, bilateral shadowing, and posterior echo pattern-were tabulated. A pathologist reviewed each case and independently recorded the following data : cell type, the presence of septum, duct dilatation,calcification, fibrosis, hyalinization, and vascularity. We analyzed the correlation of sonographic with pathologic findings. Results : There was significant correlation between increased vascularity and increased internal echo strength and between increased fibrosis and decreased internal echo strength. There was no significant correlation between internal echo homogeneity or posterior shadowing and vascularity or stromal fibrosis, nor between hyalinization or cell type and internal echo strength, homogeneity or posterior shadowing.There was correlation between absent or thin capsule and the absence of bilateral shadowing. Conclusion :Increased vascularity or decreased stromal fibrosis might be the cause of atypical fibroadenoma.

  11. Vascular lesions following radiation

    International Nuclear Information System (INIS)

    Fajardo, L.F.; Berthrong, M.

    1988-01-01

    The special radiation sensitivity of the vascular system is mainly linked to that of endothelial cells, which are perhaps the most radiation-vulnerable elements of mesenchymal tissues. Within the vascular tree, radiation injures most often capillaries, sinusoids, and small arteries, in that order. Lesions of veins are observed less often, but in certain tissues the veins are regularly damaged (e.g., intestine) or are the most affected structures (i.e., liver). Large arteries do suffer the least; however, when significant damage does occur in an elastic artery (e.g., thrombosis or rupture), it tends to be clinically significant and even fatal. Although not always demonstrable in human tissues, radiation vasculopathy generally is dose and time dependent. Like other radiation-induced lesions, the morphology in the vessels is not specific, but it is characteristic enough to be often recognizable. Vascular injury, especially by therapeutic radiation is not just a morphologic marker. It is a mediator of tissue damage; perhaps the most consistent pathogenetic mechanism in delayed radiation injury

  12. Vascular lumen formation.

    Science.gov (United States)

    Lammert, Eckhard; Axnick, Jennifer

    2012-04-01

    The vascular system developed early in evolution. It is required in large multicellular organisms for the transport of nutrients, oxygen, and waste products to and from tissues. The vascular system is composed of hollow tubes, which have a high level of complexity in vertebrates. Vasculogenesis describes the de novo formation of blood vessels, e.g., aorta formation in vertebrate embryogenesis. In contrast, angiogenesis is the formation of blood vessels from preexisting ones, e.g., sprouting of intersomitic blood vessels from the aorta. Importantly, the lumen of all blood vessels in vertebrates is lined and formed by endothelial cells. In both vasculogenesis and angiogenesis, lumen formation takes place in a cord of endothelial cells. It involves a complex molecular mechanism composed of endothelial cell repulsion at the cell-cell contacts within the endothelial cell cords, junctional rearrangement, and endothelial cell shape change. As the vascular system also participates in the course of many diseases, such as cancer, stroke, and myocardial infarction, it is important to understand and make use of the molecular mechanisms of blood vessel formation to better understand and manipulate the pathomechanisms involved.

  13. Pulmonary vascular imaging

    International Nuclear Information System (INIS)

    Fedullo, P.F.; Shure, D.

    1987-01-01

    A wide range of pulmonary vascular imaging techniques are available for the diagnostic evaluation of patients with suspected pulmonary vascular disease. The characteristics of any ideal technique would include high sensitivity and specificity, safety, simplicity, and sequential applicability. To date, no single technique meets these ideal characteristics. Conventional pulmonary angiography remains the gold standard for the diagnosis of acute thromboembolic disease despite the introduction of newer techniques such as digital subtraction angiography and magnetic resonance imaging. Improved noninvasive lower extremity venous testing methods, particularly impedance plethysmography, and ventilation-perfusion scanning can play significant roles in the noninvasive diagnosis of acute pulmonary emboli when properly applied. Ventilation-perfusion scanning may also be useful as a screening test to differentiate possible primary pulmonary hypertension from chronic thromboembolic pulmonary hypertension. And, finally, angioscopy may be a useful adjunctive technique to detect chronic thromboembolic disease and determine operability. Optimal clinical decision-making, however, will continue to require the proper interpretation of adjunctive information obtained from the less-invasive techniques, applied with an understanding of the natural history of the various forms of pulmonary vascular disease and with a knowledge of the capabilities and shortcomings of the individual techniques

  14. The adventitia: Essential role in pulmonary vascular remodeling.

    Science.gov (United States)

    Stenmark, Kurt R; Nozik-Grayck, Eva; Gerasimovskaya, Evgenia; Anwar, Adil; Li, Min; Riddle, Suzette; Frid, Maria

    2011-01-01

    A rapidly emerging concept is that the vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and comprises a variety of cells including fibroblasts, immunomodulatory cells, resident progenitor cells, vasa vasorum endothelial cells, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to then influence tone and structure of the vessel wall. Experimental data indicate that the adventitial fibroblast, the most abundant cellular constituent of adventitia, is a critical regulator of vascular wall function. In response to vascular stresses such as overdistension, hypoxia, or infection, the adventitial fibroblast is activated and undergoes phenotypic changes that include proliferation, differentiation, and production of extracellular matrix proteins and adhesion molecules, release of reactive oxygen species, chemokines, cytokines, growth factors, and metalloproteinases that, collectively, affect medial smooth muscle cell tone and growth directly and that stimulate recruitment and retention of circulating inflammatory and progenitor cells to the vessel wall. Resident dendritic cells also participate in "sensing" vascular stress and actively communicate with fibroblasts and progenitor cells to simulate repair processes that involve expansion of the vasa vasorum, which acts as a conduit for further delivery of inflammatory/progenitor cells. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of pulmonary vascular wall function and structure from the "outside in." © 2011 American Physiological Society.

  15. CaMKII in Vascular Signalling: "Friend or Foe"?

    Science.gov (United States)

    Ebenebe, Obialunanma V; Heather, Alison; Erickson, Jeffrey R

    2018-05-01

    Signalling mechanisms within and between cells of the vasculature enable function and maintain homeostasis. However, a number of these mechanisms also contribute to the pathophysiology of vascular disease states. The multifunctional signalling molecule calcium/calmodulin-dependent kinase II (CaMKII) has been shown to have critical functional effects in many tissue types. For example, CaMKII is known to have a dual role in cardiac physiology and pathology. The function of CaMKII within the vasculature is incompletely understood, but emerging evidence points to potential physiological and pathological roles. This review discusses the evidence for CaMKII signalling within the vasculature, with the aim to better understand both positive and potentially deleterious effects of CaMKII activation in vascular tissue. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  16. Pathology in Undergraduate Training Program

    Directory of Open Access Journals (Sweden)

    Shiva Raj K.C.

    2018-04-01

    Full Text Available Pathology is a study of disease which deals with etiology, pathogenesis and morphological features and the associated clinical features. Pathology acts as a bridge that fills the gap between basic sciences and clinical medicine. With proper understanding of pathological processes, one can understand the disease process. In Nepal, since the beginning of medical school teaching, Pathology as a basic science discipline and is a component of the preclinical medical school curriculum.Pathology teaching in 19th century was vague, disorganized and very little, though precious. The lectures used to be conducted by surgeons. At Barts, surgeon Sir James Paget had taught surgical pathology. The real revolution in pathology teaching began in the early 1900s when, spurred on by increasing understanding of disease mechanisms, pathology began to be accepted as a specialty in its own right.During the early and mid of 20th century, pathology teaching was a part of clinical teaching with daily, autopsy demonstration. By the late 1980s, significant change had taken place. In many medical schools, debate started regarding relevance of vigorous preclinical teaching. Then system-based approach was incorporated and traditional preclinical course had been abandoned. With this pathology teaching also began to change with pathologists being involved in teaching histology, often alongside pathology to highlight its clinical relevance. In medical schools the pathology teaching time was cut. Autopsy demonstrations, which had been so popular with generations of medical students, were becoming irregular and less well attended.Though teaching of pathology in blocks to ‘avoid fragmentation’ has disappeared in western countries; it is still practice in Nepal. In western countries there was traditional practice of teaching general pathology in the first two years and systemic pathology in the clinical years. Now pathology teaching is integrated throughout the course. A

  17. Protein Kinase C Inhibitors as Modulators of Vascular Function and Their Application in Vascular Disease

    Directory of Open Access Journals (Sweden)

    Raouf A. Khalil

    2013-03-01

    Full Text Available Blood pressure (BP is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN. In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i, which forms a complex with calmodulin, activates myosin light chain (MLC kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC. PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK and MAPK kinase (MEK, a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in

  18. Cortical myoclonus and cerebellar pathology

    NARCIS (Netherlands)

    Tijssen, MAJ; Thom, M; Ellison, DW; Wilkins, P; Barnes, D; Thompson, PD; Brown, P

    2000-01-01

    Objective To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. Background: The pathologic findings in conditions associated with cortical myoclonus commonly involve

  19. Cortical myoclonus and cerebellar pathology

    NARCIS (Netherlands)

    Tijssen, M. A.; Thom, M.; Ellison, D. W.; Wilkins, P.; Barnes, D.; Thompson, P. D.; Brown, P.

    2000-01-01

    OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve

  20. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria

    NARCIS (Netherlands)

    Halushka, Marc K.; Angelini, Annalisa; Bartoloni, Giovanni; Basso, Cristina; Batoroeva, Lubov; Bruneval, Patrick; Buja, L. Maximilian; Butany, Jagdish; d'Amati, Giulia; Fallon, John T.; Gallagher, Patrick J.; Gittenberger-de Groot, Adriana C.; Gouveia, Rosa H.; Kholova, Ivana; Kelly, Karen L.; Leone, Ornella; Litovsky, Silvio H.; Maleszewski, Joseph J.; Miller, Dylan V.; Mitchell, Richard N.; Preston, Stephen D.; Pucci, Angela; Radio, Stanley J.; Rodriguez, E. Rene; Sheppard, Mary N.; Stone, James R.; Suvarna, S. Kim; Tan, Carmela D.; Thiene, Gaetano; Veinot, John P.; van der Wal, Allard C.

    2016-01-01

    Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys-Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct

  1. Ryanodine receptor 1 and associated pathologies

    OpenAIRE

    Fauré , Julien; Lunardi , Joël; Monnier , Nicole; Marty , Isabelle

    2014-01-01

    In skeletal muscle a rise in the cytosolic calcium concentration is the first trigger able to initiate the contraction of the sarcomere. Intracellular calcium levels are tightly controlled by channels and pumps, and it is not surprising that many inherited skeletal muscle disorders arise from mutations altering the players regulating calcium ions concentration (Betzenhauser et al., 2010). In this chapter, we will focus on the pathologies linked to the sarcoplasmic reticulum calcium channel-Ry...

  2. VE-Cadherin–Mediated Epigenetic Regulation of Endothelial Gene Expression

    Science.gov (United States)

    Morini, Marco F.; Giampietro, Costanza; Corada, Monica; Pisati, Federica; Lavarone, Elisa; Cunha, Sara I.; Conze, Lei L.; O’Reilly, Nicola; Joshi, Dhira; Kjaer, Svend; George, Roger; Nye, Emma; Ma, Anqi; Jin, Jian; Mitter, Richard; Lupia, Michela; Cavallaro, Ugo; Pasini, Diego; Calado, Dinis P.

    2018-01-01

    Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased

  3. VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression.

    Science.gov (United States)

    Morini, Marco F; Giampietro, Costanza; Corada, Monica; Pisati, Federica; Lavarone, Elisa; Cunha, Sara I; Conze, Lei L; O'Reilly, Nicola; Joshi, Dhira; Kjaer, Svend; George, Roger; Nye, Emma; Ma, Anqi; Jin, Jian; Mitter, Richard; Lupia, Michela; Cavallaro, Ugo; Pasini, Diego; Calado, Dinis P; Dejana, Elisabetta; Taddei, Andrea

    2018-01-19

    The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5 , vascular endothelial-protein tyrosine phosphatase ( VE-PTP ), and von Willebrand factor ( vWf ). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5 , VE-PTP , and vWf . VEC/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5 , VE-PTP , and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. These

  4. Vascular imaging with spiral CT. The way to CY angiography

    International Nuclear Information System (INIS)

    Prokop, M.; Schaefer, C.; Kalender, W.A.; Polacin, A.; Galanski, M.

    1993-01-01

    Spiral CT is a technique that allows for high-quality two-dimensional angiographic projections and 3D imaging of vascular structures. The authors present the technical and methodological principles of the technique, including scan parameters and parameters of contrast application for various clinical imaging tasks. They present their experience with over 150 clinical cases using spiral CT angiography. Suitable applications of this technique include cogenital anomalies, aneurysms, dissections, stenoses, thrombi and vascular tumor involvement. Given a problem-adapted examination technique, pathologic changes in vessels of as little as 2 mm can be visualized. In some cases with complex vascular anatomy, spiral CT angiography can be superior to arterial angiography. (orig.) [de

  5. Hemangiomas and Vascular Malformations: A Diagnostic and Therapeutic Focus

    International Nuclear Information System (INIS)

    Neira Escobar, Fabian; Chamorro, Flor Medina; Posada Trujillo, Clara Ines

    2008-01-01

    The objective is to analyze the main epidemiological, pathophysiological, clinical,and imagenological aspects of the vascular hemangiomas and vascular malformations, emphasizing the therapeutic options. The vascular hemangiomas and malformations are the most frequent benign tumors in childhood. Their description and classification remain confusing, which makes it difficult to have an adequate approach to the diagnosis and their treatment. The radiologist has to guide the physician through the selection of the appropriate study for each patient, and characterize in detail all the injuries based on the analysis of the diagnostic modalities performed. The role of the interventionist radiologist is crucial as a part of the interdisciplinary group, which has to be involved in the treatment of these patients. Patients with this pathology, sent from medical assistance centers around the country are consulted at the Instituto Nacional de Cancerologia (Cancer Research National Institute). Based on this experience, it shows clinical and imagenological focus for the diagnosis and handling of these injuries.

  6. A neurodegenerative vascular burden index and the impact on cognition

    Directory of Open Access Journals (Sweden)

    Sebastian eHeinzel

    2014-07-01

    Full Text Available A wide range of vascular burden factors have been identified to impact vascular function and structure as indicated by carotid intima-media thickness (IMT. On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI. Since many vascular factors increase the risk of Alzheimer's disease (AD, a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages.We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102 for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication and/or blood marker data were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT and the CERAD neuropsychological battery.IMT was significantly predicted by age (standardized β = .26, sex (.09; males > females and the factors included in the VBI: obesity (.18, hypertension (.14, smoking (.08, diabetes (.07, and atherosclerosis (.05, whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT (≥1.0 mm. The VBI showed an impact on executive control (log(TMT B-A, p = .047 and a trend towards decreased global cognitive function (CERAD total score, p = .057 independent of age, sex and education.A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and

  7. Pathology Gross Photography: The Beginning of Digital Pathology.

    Science.gov (United States)

    Rampy, B Alan; Glassy, Eric F

    2015-06-01

    The underutilized practice of photographing anatomic pathology specimens from surgical pathology and autopsies is an invaluable benefit to patients, clinicians, pathologists, and students. Photographic documentation of clinical specimens is essential for the effective practice of pathology. When considering what specimens to photograph, all grossly evident pathology, absent yet expected pathologic features, and gross-only specimens should be thoroughly documented. Specimen preparation prior to photography includes proper lighting and background, wiping surfaces of blood, removing material such as tubes or bandages, orienting the specimen in a logical fashion, framing the specimen to fill the screen, positioning of probes, and using the right-sized scale. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Vascular nitric oxide: Beyond eNOS

    Directory of Open Access Journals (Sweden)

    Yingzi Zhao

    2015-10-01

    Full Text Available As the first discovered gaseous signaling molecule, nitric oxide (NO affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC to produce cyclic guanosine monophosphate (cGMP, although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA or production of cyclic inosine monophosphate (cIMP] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.

  9. Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis

    Directory of Open Access Journals (Sweden)

    Peter J Little

    2007-03-01

    Full Text Available Peter J Little1, 2, 3, Mandy L. Ballinger1, Narin Osman1,31Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia; Monash University, Departments of 2Medicine and 3Immunology, Central and Eastern Clinical School, Alfred Hospital, Melbourne, AustraliaAbstract: Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors —hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL binding are the length and sulfation pattern on the glycosaminoglycan (GAG chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.Keywords: proteoglycans, signaling, lipoproteins, atherosclerosis

  10. Targeted modulation of reactive oxygen species in the vascular endothelium.

    Science.gov (United States)

    Shuvaev, Vladimir V; Muzykantov, Vladimir R

    2011-07-15

    'Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-modified enzymes. Targeting of ROS generating enzymes (e.g., glucose oxidase) provides ROS- and site-specific models of endothelial oxidative stress, whereas targeting of antioxidant enzymes SOD and catalase offers site-specific quenching of superoxide anion and H(2)O(2). These targeted antioxidant interventions help to clarify specific role of endothelial ROS in vascular and pulmonary pathologies and provide basis for design of targeted therapeutics for treatment of these pathologies. In particular, antibody/catalase conjugates alleviate acute lung ischemia/reperfusion injury, whereas antibody/SOD conjugates inhibit ROS-mediated vasoconstriction and inflammatory endothelial signaling. Encapsulation in protease-resistant, ROS-permeable carriers targeted to endothelium prolongs protective effects of antioxidant enzymes, further diversifying the means for targeted modulation of endothelial ROS. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Pancreatic neuroendocrine tumours: correlation between MSCT features and pathological classification

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Yanji; Dong, Zhi; Li, Zi-Ping; Feng, Shi-Ting [The First Affiliated Hospital, Sun Yat-Sen University, Department of Radiology, Guangzhou, Guangdong (China); Chen, Jie [The First Affiliated Hospital, Sun Yat-Sen University, Department of Gastroenterology, Guangzhou, Guangdong (China); Chan, Tao; Chen, Minhu [Union Hospital, Hong Kong, Medical Imaging Department, Shatin, N.T. (China); Lin, Yuan [The First Affiliated Hospital, Sun Yat-Sen University, Department of Pathology, Guangzhou, Guangdong (China)

    2014-11-15

    We aimed to evaluate the multi-slice computed tomography (MSCT) features of pancreatic neuroendocrine neoplasms (P-NENs) and analyse the correlation between the MSCT features and pathological classification of P-NENs. Forty-one patients, preoperatively investigated by MSCT and subsequently operated on with a histological diagnosis of P-NENs, were included. Various MSCT features of the primary tumour, lymph node, and distant metastasis were analysed. The relationship between MSCT features and pathologic classification of P-NENs was analysed with univariate and multivariate models. Contrast-enhanced images showed significant differences among the three grades of tumours in the absolute enhancement (P = 0.013) and relative enhancement (P = 0.025) at the arterial phase. Univariate analysis revealed statistically significant differences among the tumours of different grades (based on World Health Organization [WHO] 2010 classification) in tumour size (P = 0.001), tumour contour (P < 0.001), cystic necrosis (P = 0.001), tumour boundary (P = 0.003), dilatation of the main pancreatic duct (P = 0.001), peripancreatic tissue or vascular invasion (P < 0.001), lymphadenopathy (P = 0.011), and distant metastasis (P = 0.012). Multivariate analysis suggested that only peripancreatic tissue or vascular invasion (HR 3.934, 95 % CI, 0.426-7.442, P = 0.028) was significantly associated with WHO 2010 pathological classification. MSCT is helpful in evaluating the pathological classification of P-NENs. (orig.)

  12. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Steffensen, Karina Dahl

    2012-01-01

    Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions s...

  13. Pathological gambling: An overview

    Directory of Open Access Journals (Sweden)

    Shalini Singh

    2017-01-01

    Full Text Available Gambling activities are popular as a form of recreation and have been a source of income for many people worldwide. Although gambling has been common across continents and time, and a subset of individuals experience problems with gambling. This review attempts to provide an overview of problem gambling for clinicians who are likely to encounter such patients in their practice. The review discusses the relevance, nosology, and epidemiology of gambling. We also discuss the associated comorbidities and principles of management of pathological gambling.

  14. Marketing the pathology practice.

    Science.gov (United States)

    Berkowitz, E N

    1995-07-01

    Effective marketing of the pathology practice is essential in the face of an increasingly competitive market. Successful marketing begins with a market-driven planning process. As opposed to the traditional planning process used in health care organizations, a market-driven approach is externally driven. Implementing a market-driven plan also requires recognition of the definition of the service. Each market to which pathologists direct their service defines the service differently. Recognition of these different service definitions and creation of a product to meet these needs could lead to competitive advantages in the marketplace.

  15. Hypothesis: the regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia.

    Science.gov (United States)

    Devereux, Diana; Ikomi-Kumm, Julie

    2013-03-01

    The regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia is a hypothesis, which proposes an inherent operative system in homo sapiens that allows central nervous system and endocrine-mediated vascular system adaption to variables in partial pressure of oxygen, pH and body composition, while maintaining sufficient oxygen saturation for the immune system and ensuring protection of major organs in hypoxic and suboptimal conditions. While acknowledging the importance of the Henderson-Hasselbalch equation in the regulation of acid base balance, the hypothesis seeks to define the specific neuroendocrine/vascular mechanisms at work in regulating acid base balance in hypoxia and infection. The SIA (serotonin-immune-adrenergic) system is proposed as a working model, which allows central nervous system and endocrine-mediated macro- and micro vascular 'fine tuning'. The neurotransmitter serotonin serves as a 'hypoxic sensor' in concert with other operators to orchestrate homeostatic balance in normal and pathological states. The SIA system finely regulates oxygen, fuel and metabolic buffering systems at local sites to ensure optimum conditions for the immune response. The SIA system is fragile and its operation may be affected by infection, stress, diet, environmental toxins and lack of exercise. The hypothesis provides new insight in the area of neuro-gastroenterology, and emphasizes the importance of diet and nutrition as a complement in the treatment of infection, as well as the normalization of intestinal flora following antibiotic therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Multinephron dynamics on the renal vascular network

    DEFF Research Database (Denmark)

    Marsh, Donald J; Wexler, Anthony S; Brazhe, Alexey

    2012-01-01

    Tubuloglomerular feedback (TGF) and the myogenic mechanism combine in each nephron to regulate blood flow and glomerular filtration rate. Both mechanisms are non-linear, generate self-sustained oscillations, and interact as their signals converge on arteriolar smooth muscle, forming a regulatory...... clusters. In-phase synchronization predominated among nephrons separated by 1 or 3 vascular nodes, and anti-phase synchronization for 5 or 7 nodes of separation. Nephron dynamics were irregular and contained low frequency fluctuations. Results are consistent with simultaneous blood flow measurements...... of both mechanisms in the regulatory ensemble, to examine the effects of network structure on nephron synchronization. Symmetry, as a property of a network, facilitates synchronization. Nephrons received blood from a symmetric electrically conductive vascular tree. Symmetry was created by using identical...

  17. Pathology of the vestibulocochlear nerve

    Energy Technology Data Exchange (ETDEWEB)

    De Foer, Bert [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: bert.defoer@GZA.be; Kenis, Christoph [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: christophkenis@hotmail.com; Van Melkebeke, Deborah [Department of Neurology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Deborah.vanmelkebeke@Ugent.be; Vercruysse, Jean-Philippe [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: jphver@yahoo.com; Somers, Thomas [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Thomas.somers@GZA.be; Pouillon, Marc [Department of Radiology, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: marc.pouillon@GZA.be; Offeciers, Erwin [University Department of ENT, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium)], E-mail: Erwin.offeciers@GZA.be; Casselman, Jan W. [Department of Radiology, AZ Sint-Jan AV Hospital, Ruddershove 10, Bruges (Belgium); Consultant Radiologist, Sint-Augustinus Hospital, Oosterveldlaan 24, 2610 Wilrijk (Belgium); Academic Consultent, University of Ghent (Belgium)], E-mail: jan.casselman@azbrugge.be

    2010-05-15

    There is a large scala of pathology affecting the vestibulocochlear nerve. Magnetic resonance imaging is the method of choice for the investigation of pathology of the vestibulocochlear nerve. Congenital pathology mainly consists of agenesis or hypoplasia of the vestibulocochlear nerve. Tumoral pathology affecting the vestibulocochlear nerve is most frequently located in the internal auditory canal or cerebellopontine angle. Schwannoma of the vestibulocochlear nerve is the most frequently found tumoral lesion followed by meningeoma, arachnoid cyst and epidermoid cyst. The most frequently encountered pathologies as well as some more rare entities are discussed in this chapter.

  18. Pathology of the vestibulocochlear nerve

    International Nuclear Information System (INIS)

    De Foer, Bert; Kenis, Christoph; Van Melkebeke, Deborah; Vercruysse, Jean-Philippe; Somers, Thomas; Pouillon, Marc; Offeciers, Erwin; Casselman, Jan W.

    2010-01-01

    There is a large scala of pathology affecting the vestibulocochlear nerve. Magnetic resonance imaging is the method of choice for the investigation of pathology of the vestibulocochlear nerve. Congenital pathology mainly consists of agenesis or hypoplasia of the vestibulocochlear nerve. Tumoral pathology affecting the vestibulocochlear nerve is most frequently located in the internal auditory canal or cerebellopontine angle. Schwannoma of the vestibulocochlear nerve is the most frequently found tumoral lesion followed by meningeoma, arachnoid cyst and epidermoid cyst. The most frequently encountered pathologies as well as some more rare entities are discussed in this chapter.

  19. Anesthesia and Tau Pathology

    Science.gov (United States)

    Whittington, Robert A.; Bretteville, Alexis; Dickler, Maya F.; Planel, Emmanuel

    2013-01-01

    Alzheimer’s disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration. PMID:23535147

  20. Fractal Branching in Vascular Trees and Networks by VESsel GENeration Analysis (VESGEN)

    Science.gov (United States)

    Parsons-Wingerter, Patricia A.

    2016-01-01

    Vascular patterning offers an informative multi-scale, fractal readout of regulatory signaling by complex molecular pathways. Understanding such molecular crosstalk is important for physiological, pathological and therapeutic research in Space Biology and Astronaut countermeasures. When mapped out and quantified by NASA's innovative VESsel GENeration Analysis (VESGEN) software, remodeling vascular patterns become useful biomarkers that advance out understanding of the response of biology and human health to challenges such as microgravity and radiation in space environments.

  1. Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury.

    Science.gov (United States)

    Gyoneva, Stefka; Kim, Daniel; Katsumoto, Atsuko; Kokiko-Cochran, O Nicole; Lamb, Bruce T; Ransohoff, Richard M

    2015-12-03

    Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain. Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.

  2. Interventional vascular radiology

    International Nuclear Information System (INIS)

    Yune, H.Y.

    1984-01-01

    The papers published during this past year in the area of interventional vascular radiology presented some useful modifications and further experiences both in the area of thromboembolic therapy and in dilation and thrombolysis, but no new techniques. As an introductory subject, an excellent monograph reviewing the current spectrum of pharmacoangiography was presented in Radiographics. Although the presented material is primarily in diagnostic application of various pharmacologic agents used today to facilitate demonstration of certain diagnostic criteria of various disease processes, both vasodilatory and vasoconstrictive reaction to these agents are widely used in various therapeutic vascular procedures. This monograph should be reviewed by every angiographer whether or not he or she performs interventional procedures, and it would be very convenient to have this table available in the angiography suite. In a related subject, Bookstein and co-workers have written an excellent review concerning pharmacologic manipulations of various blood coagulative parameters during angiography. Understanding the proper method of manipulation of the bloodclotting factors during angiography, and especially during interventional angiography, is extremely important. Particularly, the method of manipulating the coagulation with the use of heparin and protamine and modification of the platelet activity by using aspirin and dipyridamole are succinctly reviewed. The systemic and selective thrombolytic activities of streptokianse are also discussed

  3. Vascular dysfunction in preeclampsia.

    Science.gov (United States)

    Brennan, Lesley J; Morton, Jude S; Davidge, Sandra T

    2014-01-01

    Preeclampsia is a complex disorder which affects an estimated 5% of all pregnancies worldwide. It is diagnosed by hypertension in the presence of proteinuria after the 20th week of pregnancy and is a prominent cause of maternal morbidity and mortality. As delivery is currently the only known treatment, preeclampsia is also a leading cause of preterm delivery. Preeclampsia is associated with maternal vascular dysfunction, leading to serious cardiovascular risk both during and following pregnancy. Endothelial dysfunction, resulting in increased peripheral resistance, is an integral part of the maternal syndrome. While the cause of preeclampsia remains unknown, placental ischemia resulting from aberrant placentation is a fundamental characteristic of the disorder. Poor placentation is believed to stimulate the release of a number of factors including pro- and antiangiogenic factors and inflammatory activators into the maternal systemic circulation. These factors are critical mediators of vascular function and impact the endothelium in distinctive ways, including enhanced endothelial oxidative stress. The mechanisms of action and the consequences on the maternal vasculature will be discussed in this review. © 2013 John Wiley & Sons Ltd.

  4. A quantitative brain map of experimental cerebral malaria pathology.

    Directory of Open Access Journals (Sweden)

    Patrick Strangward

    2017-03-01

    Full Text Available The murine model of experimental cerebral malaria (ECM has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM. However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.

  5. A quantitative brain map of experimental cerebral malaria pathology.

    Science.gov (United States)

    Strangward, Patrick; Haley, Michael J; Shaw, Tovah N; Schwartz, Jean-Marc; Greig, Rachel; Mironov, Aleksandr; de Souza, J Brian; Cruickshank, Sheena M; Craig, Alister G; Milner, Danny A; Allan, Stuart M; Couper, Kevin N

    2017-03-01

    The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.

  6. The influence of perivascular adipose tissue on vascular homeostasis.

    Science.gov (United States)

    Szasz, Theodora; Bomfim, Gisele Facholi; Webb, R Clinton

    2013-01-01

    The perivascular adipose tissue (PVAT) is now recognized as an active contributor to vascular function. Adipocytes and stromal cells contained within PVAT are a source of an ever-growing list of molecules with varied paracrine effects on the underlying smooth muscle and endothelial cells, including adipokines, cytokines, reactive oxygen species, and gaseous compounds. Their secretion is regulated by systemic or local cues and modulates complex processes, including vascular contraction and relaxation, smooth muscle cell proliferation and migration, and vascular inflammation. Recent evidence demonstrates that metabolic and cardiovascular diseases alter the morphological and secretory characteristics of PVAT, with notable consequences. In obesity and diabetes, the expanded PVAT contributes to vascular insulin resistance. PVAT-derived cytokines may influence key steps of atherogenesis. The physiological anticontractile effect of PVAT is severely diminished in hypertension. Above all, a common denominator of the PVAT dysfunction in all these conditions is the immune cell infiltration, which triggers the subsequent inflammation, oxidative stress, and hypoxic processes to promote vascular dysfunction. In this review, we discuss the currently known mechanisms by which the PVAT influences blood vessel function. The important discoveries in the study of PVAT that have been made in recent years need to be further advanced, to identify the mechanisms of the anticontractile effects of PVAT, to explore the vascular-bed and species differences in PVAT function, to understand the regulation of PVAT secretion of mediators, and finally, to uncover ways to ameliorate cardiovascular disease by targeting therapeutic approaches to PVAT.

  7. Angiographic findings of congenital vascular malformation in soft tissue

    International Nuclear Information System (INIS)

    Choi, Dae Seob; Park, Jae Hyung; Han, Joon Koo; Chung, Jin Wook; Moon, Woo Kyung; Han, Man Chung

    1994-01-01

    We evaluated the clinical, plain radiographic, and angiographic findings of congenital vascular malformation of the soft tissue. Retrospective analysis was performed in 36 patients. Pathological diagnosis was done in 25 patients by surgery and the others were clinically and angiographically diagnosed. On the basis of angiographic findings, we classified the lesions to three groups as arteriovenous malformation (AVM), hemangioma, and venous malformation. In pathologically proven 25 cases, we compared the angiographic diagnosis with the pathologic diagnosis. By angiographic classification, AVM was 13 cases, hemangioma 16 cases, and venous malformation 7 cases. The locations of the lesions were upper extremities in 14 cases, lower extremities in 20 cases, both extremities in 1 case, and back in 1 case. Clinical findings were bruit and thrill in 13 cases(12 AVMs,1 hemangioma) and varicosities in 16 cases(11 AVMs, 3 hemangiomas and 2 venous malformations). The varicosities in AVM were pulsating nature, but not in hemangioma and venous malformation. The concordance rate of the angiographic and pathologic diagnosis was 100%(6/6) in AVM, 71%(10/14) in hemangioma and 60% (3/5) in venous malformation. We think that angiography is an essential study for accurate diagnosis and appropriate treatment of congenital vascular malformation

  8. Magnetic resonance imaging of intracavernous pathology

    Energy Technology Data Exchange (ETDEWEB)

    Komiyama, Masaki; Yasui, Toshihiro; Yagura, Hisatsugu; Fu, Yoshihiko; Baba, Mitsuru [Baba Memorial Hospital, Sakai, Osaka (Japan); Hakuba, Akira; Nishimura, Shuro

    1989-07-01

    To evaluate the usefulness of magnetic resonance (MR) imaging of intracavernous pathology, T{sub 1}-weighted spin echo images of four vascular lesions and 10 neoplastic lesions with surgically confirmed cavernous sinus (CS) invasion were reviewed retrospectively. In one case of traumatic carotid-cavernous fistula (CCF) and one of dural arteriovenous malformation (AVM), the internal carotid artery (ICA) and rapid shunted flow were depicted as signal voids, and the relationship between the ICA and shunted flow was clearly shown. Normal venous flow appeared as a low-intensity area and was observed even in the presence of the CCF and dural AVM. In two cases of thrombosed aneurysms, the thrombosis was clearly demonstrated, along with patent arterial flow in one case; in the other case, however, it was impossible to differentiate patent arterial flow from calcification. The intensity of all neoplastic lesions was similar to that of the cerebral cortex. The relationship between the ICA and the tumors was clearly demonstrated. The visual pathways were also plainly shown unless they were involved, or markedly compressed, by tumor. CS invasion was strongly associated with four findings: (1) encasement of the ICA by the tumor; (2) marked displacement of the ICA; (3) absence of low intensity, which reflects normal venous flow, in the CS; and (4) extension of extrasellar tumors to the medial wall or of intrasellar tumors to the lateral wall. MR imaging was judged promising in the evaluation of intracavernous pathology. (author).

  9. Vascular pattern formation in plants.

    Science.gov (United States)

    Scarpella, Enrico; Helariutta, Ykä

    2010-01-01

    Reticulate tissue systems exist in most multicellular organisms, and the principles underlying the formation of cellular networks have fascinated philosophers, mathematicians, and biologists for centuries. In particular, the beautiful and varied arrangements of vascular tissues in plants have intrigued mankind since antiquity, yet the organizing signals have remained elusive. Plant vascular tissues form systems of interconnected cell files throughout the plant body. Vascular cells are aligned with one another along continuous lines, and vascular tissues differentiate at reproducible positions within organ environments. However, neither the precise path of vascular differentiation nor the exact geometry of vascular networks is fixed or immutable. Several recent advances converge to reconcile the seemingly conflicting predictability and plasticity of vascular tissue patterns. A control mechanism in which an apical-basal flow of signal establishes a basic coordinate system for body axis formation and vascular strand differentiation, and in which a superimposed level of radial organizing cues elaborates cell patterns, would generate a reproducible tissue configuration in the context of an underlying robust, self-organizing structure, and account for the simultaneous regularity and flexibility of vascular tissue patterns. Copyright 2010 Elsevier Inc. All rights reserved.

  10. Sida rhomboidea.Roxb aqueous extract down-regulates in vivo expression of vascular cell adhesion molecules in atherogenic rats and inhibits in vitro macrophage differentiation and foam cell formation.

    Science.gov (United States)

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Salunke, Sunita P; Devkar, Ranjitsinh V; Ramachandran, A V

    2012-10-01

    The present study evaluates efficacy of Sida rhomboidea.Roxb (SR) leaves extract in ameliorating experimental atherosclerosis using in vitro and in vivo experimental models. Atherogenic (ATH) diet fed rats recorded significant increment in the serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very LDL (VLDL), autoantibody against oxidized LDL (Ox-LDL), markers of LDL oxidation and decrement in high-density lipoprotein (HDL) along with increment in aortic TC and TG. The ex vivo LDL oxidation assay revealed an increased susceptibility of LDL isolated from ATH rats to undergo copper mediated oxidation. These set of changes were minimized by simultaneous co-supplementation of SR extract to ATH diet fed rats. Histopathology of aorta and immunolocalization studies recorded pronounced atheromatous plaque formation, vascular calcification, significant elastin derangements and higher expression of macrophage surface marker (F4/80), vascular cell adhesion molecule-1 (VCAM-1) and p-selectin in ATH rats. Whereas, ATH+SR rats depicted minimal evidence of atheromatous plaque formation, calcium deposition, distortion/defragmentation of elastin and accumulation of macrophages along with lowered expression of VCAM-1 and P-selectin compared to ATH rats. Further, monocyte to macrophage differentiation and in vitro foam cell formation were significantly attenuated in presence of SR extract. In conclusion, SR extract has the potency of controlling experimental atherosclerosis and can be used as promising herbal supplement in combating atherosclerosis.

  11. Shaping the landscape: Metabolic regulation of S1P gradients

    Science.gov (United States)

    Olivera, Ana; Allende, Maria Laura; Proia, Richard L.

    2012-01-01

    Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology. PMID:22735358

  12. Vascular measurements correlate with estrogen receptor status

    International Nuclear Information System (INIS)

    Lloyd, Mark C; Alfarouk, Khalid O; Verduzco, Daniel; Bui, Marilyn M; Gillies, Robert J; Ibrahim, Muntaser E; Brown, Joel S; Gatenby, Robert A

    2014-01-01

    Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis. This study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings. ANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R 2 = 39%; p < 0.003 and R 2 = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size. We conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti

  13. The Pathology Laboratory Act 2007 explained.

    Science.gov (United States)

    Looi, Lai-Meng

    2008-06-01

    laboratory practices are left to be specified by the Director-General of Health, providing for a formal recognition process and room for revision as pathology practices evolve. Encompassed in the responsibilities of the licensee is the requirement that samples are received and results issued through, and management vested in, a registered medical or dental practitioner. This effectively prohibits "walk-ins" to the laboratory and indiscriminate public screening. The requirement for a person-in-charge in accordance with class and speciality of laboratory ensures that the laboratory is under the charge of the pathology profession. Examined carefully, the requirements of the Act are similar to laboratory accreditation, but are backed by legislation. Many of these details will be spelt out in the Regulations, and these in turn are likely to fall back on National professional guidelines, as accreditation does. Although not at first obvious, enforcement of the Act is based on self-regulation by pathology laboratory professionals. Sincere professional input is thus required to embrace its philosophy, ensure rational and transparent enforcement of legislation, and develop National guidelines for good pathology practices upon which enforcement may be based.

  14. Methods for the correction of vascular artifacts in PET O-15 water brain-mapping studies

    Science.gov (United States)

    Chen, Kewei; Reiman, E. M.; Lawson, M.; Yun, Lang-sheng; Bandy, D.; Palant, A.

    1996-12-01

    While positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) can be used to map brain regions that are involved in normal and pathological human behaviors, measurements in the anteromedial temporal lobe can be confounded by the combined effects of radiotracer activity in neighboring arteries and partial-volume averaging. The authors now describe two simple methods to address this vascular artifact. One method utilizes the early frames of a dynamic PET study, while the other method utilizes a coregistered magnetic resonance image (MRI) to characterize the vascular region of interest (VROI). Both methods subsequently assign a common value to each pixel in the VROI for the control (baseline) scan and the activation scan. To study the vascular artifact and to demonstrate the ability of the proposed methods correcting the vascular artifact, four dynamic PET scans were performed in a single subject during the same behavioral state. For each of the four scans, a vascular scan containing vascular activity was computed as the summation of the images acquired 0-60 s after radiotracer administration, and a control scan containing minimal vascular activity was computed as the summation of the images acquired 20-80 s after radiotracer administration. t-score maps calculated from the four pairs of vascular and control scans were used to characterize regional blood flow differences related to vascular activity before and after the application of each vascular artifact correction method. Both methods eliminated the observed differences in vascular activity, as well as the vascular artifact observed in the anteromedial temporal lobes. Using PET data from a study of normal human emotion, these methods permitted the authors to identify rCBF increases in the anteromedial temporal lobe free from the potentially confounding, combined effects of vascular activity and partial-volume averaging.

  15. Methods for the correction of vascular artifacts in PET O-15 water brain-mapping studies

    International Nuclear Information System (INIS)

    Chen, K.; Reiman, E.M.; Good Samaritan Regional Medical Center, Phoenix, AZ; Lawson, M.; Yun, L.S.; Bandy, D.

    1996-01-01

    While positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) can be used to map brain regions that are involved in normal and pathological human behaviors, measurements in the anteromedial temporal lobe can be confounded by the combined effects of radiotracer activity in neighboring arteries and partial-volume averaging. The authors now describe two simple methods to address this vascular artifact. One method utilizes the early frames of a dynamic PET study, while the other method utilizes a coregistered magnetic resonance image (MRI) to characterize the vascular region of interest (VROI). Both methods subsequently assign a common value to each pixel in the VROI for the control scan and the activation scan. To study the vascular artifact and to demonstrate the ability of the proposed methods correcting the vascular artifact, four dynamic PET scans were performed in a single subject during the same behavioral state. For each of the four scans, a vascular scan containing vascular activity was computed as the summation of the images acquired 0--60 s after radiotracer administrations, and a control scan containing minimal vascular activity was computed as the summation of the images acquired 20--80 s after radiotracer administration. t-score maps calculated from the four pairs of vascular and control scans were used to characterize regional blood flow differences related to vascular activity before and after the applications of each vascular artifact correction method. Both methods eliminated the observed differences in vascular activity, as well as the vascular artifact observed in the anteromedial temporal lobes. Using PET data from a study of normal human emotion, these methods permitted us to identify rCBF increases in the anteromedial temporal lobe free from the potentially confounding, combined effects of vascular activity and partial-volume averaging

  16. Coronarography in pathologic morphology

    International Nuclear Information System (INIS)

    Rozenberg, V.D.; Nepomnyashchikh, L.M.; Borodin, Yu.I.

    1987-01-01

    Of many years experience of the authors and data in world literature on post mortal coronarography during the most important general pathological processes in heart have been generalized in the monograph. Problems of radioanatomy of coronary artery were considered and data on use of postmortal coronarography in terms of correlation together with selective in-life coronarography are given. Much place takes the description of main coronarography semiotics of obstructive atherosclerosis injuries of the heart coronal system, compensation and decompensation processes of broken coronary circulation. Results of coronarography investigations in geronitogenesis as well as in sudden death are presented. Electrocardiographic-coronarographic and pathomorphologic parallels, clinical-anatomical diagnostical symptomocomplex - syndrom of menocoronary ''robbing'' are elucidated in detail. Technology of different techniques of postmortal coronarography in order to investigate macro-, microhemocirculation heart bed are described in detail as well as techniques of coronarogramm analysis which permits to use the monograph as a manual

  17. Additive Manufacturing of Vascular Grafts and Vascularized Tissue Constructs.

    Science.gov (United States)

    Elomaa, Laura; Yang, Yunzhi Peter

    2017-10-01

    There is a great need for engineered vascular grafts among patients with cardiovascular diseases who are in need of bypass therapy and lack autologous healthy blood vessels. In addition, because of the severe worldwide shortage of organ donors, there is an increasing need for engineered vascularized tissue constructs as an alternative to organ transplants. Additive manufacturing (AM) offers great advantages and flexibility of fabrication of cell-laden, multimaterial, and anatomically shaped vascular grafts and vascularized tissue constructs. Various inkjet-, extrusion-, and photocrosslinking-based AM techniques have been applied to the fabrication of both self-standing vascular grafts and porous, vascularized tissue constructs. This review discusses the state-of-the-art research on the use of AM for vascular applications and the key criteria for biomaterials in the AM of both acellular and cellular constructs. We envision that new smart printing materials that can adapt to their environment and encourage rapid endothelialization and remodeling will be the key factor in the future for the successful AM of personalized and dynamic vascular tissue applications.

  18. Pathological responses to terrorism.

    Science.gov (United States)

    Yehuda, Rachel; Bryant, Richard; Marmar, Charles; Zohar, Joseph

    2005-10-01

    Many important gains have been made in understanding PTSD and other responses to trauma as a result of neuroscience-based observations. Yet there are many gaps in our knowledge that currently impede our ability to predict those who will develop pathologic responses. Such knowledge is essential for developing appropriate strategies for mounting a mental health response in the aftermath of terrorism and for facilitating the recovery of individuals and society. This paper reviews clinical and biological studies that have led to an identification of pathologic responses following psychological trauma, including terrorism, and highlights areas of future-research. It is important to not only determine risk factors for the development of short- and long-term mental health responses to terrorism, but also apply these risk factors to the prediction of such responses on an individual level. It is also critical to consider the full spectrum of responses to terrorism, as well as the interplay between biological and psychological variables that contribute to these responses. Finally, it is essential to remove the barriers to collecting data in the aftermath of trauma by creating a culture of education in which the academic community can communicate to the public what is and is not known so that survivors of trauma and terrorism will understand the value of their participation in research to the generation of useful knowledge, and by maintaining the acquisition of knowledge as a priority for the government and those involved in the immediate delivery of services in the aftermath of large-scale disaster or trauma.

  19. Cerebral Vascular Injury in Traumatic Brain Injury.

    Science.gov (United States)

    Kenney, Kimbra; Amyot, Franck; Haber, Margalit; Pronger, Angela; Bogoslovsky, Tanya; Moore, Carol; Diaz-Arrastia, Ramon

    2016-01-01

    Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI. Published by Elsevier Inc.

  20. T cells in vascular inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Lucas L Lintermans

    2014-10-01

    Full Text Available Inflammation of the human vasculature is a manifestation of many different diseases ranging from systemic autoimmune diseases to chronic inflammatory diseases, in which multiple types of immune cells are involved. For both autoimmune diseases and chronic inflammatory diseases several observations support a key role for T lymphocytes in these disease pathologies, but the underlying mechanisms are poorly understood. Previous studies in several au