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Sample records for vascular remodeling electronic

  1. Vascular remodeling and mineralocorticoids.

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    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.

  2. Vascular Remodeling in Experimental Hypertension

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    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.

  3. Progenitor cells in pulmonary vascular remodeling

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    Yeager, Michael E.; Frid, Maria G.; Stenmark, Kurt R.

    2011-01-01

    Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow–derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow–derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure. PMID:22034593

  4. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

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    Ghobadi, G.; Bartelds, B.; van der Veen, S. J.; Dickinson, M. G.; Brandenburg, S.; Berger, R. M. F.; Langendijk, J. A.; Coppes, R. P.; van Luijk, P.

    Background Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an

  5. VASCULAR REMODELING IN HYPERTENSION: ANGIOGENESIS FEATURES

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    L. A. Haisheva

    2014-07-01

    Full Text Available Aim — cross-sectional study of changes in various segments of the vascular bed in arterial hypertension (AH, defining the role of inducers and inhibitors of angiogenesis in these processes.Materials and methods. The study included 99 patients with arterial hypertension of I–II degree, average age of 63.2 ± 2.6 years, diseaseduration 9.2 ± 7.2 years.Results. It was found that patients with arterial hypertension have disorders in all segments of vascular bed: endothelial dysfunction (highvWF, microcirculatory disorders, and increased pulse wave velocity (PWV of elastic-type vessels. The level of angioginesis factors doesnot depend on such parameters as gender, age, body mass index. Smoking and duration of hypertension influence on vascular endothelialgrowth factor raise and endostatin levels are higher in patients with family history of cardiovascular diseases. Duration of disease is directlycorrelated with microcirculatory disorders and the PWV, correlation between microcirculatory disorders and pulse wave velocity indicatetheir common processes.

  6. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

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    Pier Andrea Nicolosi

    2016-01-01

    Full Text Available Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc. The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment.

  7. Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.

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    Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina; Heeb, Lukas E M; Hassan, Iman F; Veach, Darren R; Keshari, Kayvan R; Gutin, Philip H; Scheinberg, David A; McDevitt, Michael R

    2016-11-01

    Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225 Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225 Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225 Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  8. New aspects of vascular remodelling: the involvement of all vascular cell types.

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    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.

  9. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

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    Stenmark, Kurt R; Fagan, Karen A; Frid, Maria G

    2006-09-29

    Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

  10. Regulator of calcineurin 1 mediates pathological vascular wall remodeling

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    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

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

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    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.

  12. VASCULAR REMODELING AND HEART RATE VARIABILITY IN DIFFERENT ANTIHYPERTENSIVE THERAPIES

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    E. D. Golovanova

    2008-01-01

    Full Text Available Aim. To study the effect of the long-term antihypertensive monotherapy with indapamide (Arifon Retard, 1,5 mg/d, metoprolol tartrate (Egilok Retard, 50 mg/d and combined therapy with indapamide and perindopril (Noliprel Forte, 1 tab/d: perindopril 4 mg and indapamide 1,25 mg on pulse wave velocity (PWV, cardio-ankle vascular index (CAVI and the sympathetic system activity.Material and methods. 88 patients, aged 30-59 y.o. (32 normotensive patients, 56 with arterial hypertension [HT] of 1-2 grades were examined. Biological age (BA was determined by the linear regression and the vascular wall age (VWA was estimated with the use of volume sphygmography (“VaSera-1000”, “Fucuda Denshi”, Japan. 39 patients with HT were randomized into 3 parallel groups with studied therapies lasted for 6 months. PWV, CAVI of the vessels of elastic, muscular and mixed types, blood pressure, measured in upper and lower extremities and heart rate variability (HRV were determined before and at the end of the therapies.Results. BA and VWA were elevated in all of patients with HT as compared with normotensive patients. The reduction in PWV and CAVI of the vessels of elastic and mixed types, HRV increase were found in patients with Arifon Retard monotherapy. Monotherapy with metoprolol significantly improved HVR without any influence on the vascular remodeling. Noliprel Forte significantly decreased in blood pressure in the upper and lower extremities, PWV and CAVI of the vessels of all types, decreased in VWA and increased in parasympathetic drive.Conclusion. Long-term therapy with Arifon Retard and Noliprel Forte resulted in decrease in vascular remodeling and increase in HRV simultaneously with significant antihypertensive effect in patients with HT. Metoprolol low doses therapy resulted in normalization of autonomic drive independently on antihypertensive action.

  13. Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells

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    Jie Su

    2015-01-01

    Full Text Available Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II- induced proliferation and migration of vascular smooth muscle cells (VSMCs. Dichlorofluorescein diacetate (DCFH-DA staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS.

  14. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

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    Gao, Fu [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Chambon, Pierre [Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U596, ULP, Collége de France) and Institut Clinique de la Souris, ILLKIRCH, Strasbourg (France); Tellides, George [Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (United States); Kong, Wei [Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing (China); Zhang, Xiaoming, E-mail: rmygxgwk@163.com [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Li, Wei [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China)

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  15. Splenectomy Is Modifying the Vascular Remodeling of Thrombosis

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    Frey, Maria K.; Alias, Sherin; Winter, Max P.; Redwan, Bassam; Stübiger, Gerald; Panzenboeck, Adelheid; Alimohammadi, Arman; Bonderman, Diana; Jakowitsch, Johannes; Bergmeister, Helga; Bochkov, Valery; Preissner, Klaus T.; Lang, Irene M.

    2014-01-01

    Background Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. Methods and Results We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (CTEPH), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte–platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine‐enriched phospholipids specifically inhibited endothelial proliferation and sprouting. Conclusions After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in CTEPH. PMID:24584745

  16. Type VIII collagen is elevated in diseases associated with angiogenesis and vascular remodeling

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    Hansen, N. U. B.; Willumsen, N.; Bülow Sand, Jannie Marie

    2016-01-01

    Objectives Type VIII collagen is involved in angiogenesis and remodeling of arteries. We hypothesized that type VIII collagen was upregulated in diseases associated with vascular remodeling, e.g. pulmonary fibrosis and cancer. In this paper we present the development and validation of a competitive...

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

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    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

  18. 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.

  19. Interleukin-17A and vascular remodelling in severe asthma; lack of evidence for a direct role.

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    Panariti, A; Baglole, C J; Sanchez, V; Eidelman, D H; Hussain, S; Olivenstein, R; Martin, J G; Hamid, Q

    2018-04-01

    Bronchial vascular remodelling may contribute to the severity of airway narrowing through mucosal congestion. Interleukin (IL)-17A is associated with the most severe asthmatic phenotype but whether it might contribute to vascular remodelling is uncertain. To assess vascular remodelling in severe asthma and whether IL-17A directly or indirectly may cause endothelial cell activation and angiogenesis. Bronchial vascularization was quantified in asthmatic subjects, COPD and healthy subjects together with the number of IL-17A + cells as well as the concentration of angiogenic factors in the sputum. The effect of IL-17A on in vitro angiogenesis, cell migration and endothelial permeability was assessed directly on primary human lung microvascular endothelial cells (HMVEC-L) or indirectly with conditioned medium derived from normal bronchial epithelial cells (NHBEC), fibroblasts (NHBF) and airway smooth muscle cells (ASMC) after IL-17A stimulation. Severe asthmatics have increased vascularity compared to the other groups, which correlates positively with the concentrations of angiogenic factors in sputum. Interestingly, we demonstrated that increased bronchial vascularity correlates positively with the number of subepithelial IL-17A + cells. However IL-17A had no direct effect on HMVEC-L function but it enhanced endothelial tube formation and cell migration through the production of angiogenic factors by NHBE and ASMC. Our results shed light on the role of IL-17A in vascular remodelling, most likely through stimulating the synthesis of other angiogenic factors. Knowledge of these pathways may aid in the identification of new therapeutic targets. © 2018 John Wiley & Sons Ltd.

  20. Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling.

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    Liu, Cun-Fei; Zhang, Jia; Shen, Kai; Gao, Ping-Jin; Wang, Hai-Ya; Jin, Xin; Meng, Chao; Fang, Ning-Yuan

    2015-04-01

    Vascular adventitia and adventitia‑derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti‑oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII‑induced vascular remodeling in vivo. Adenoviruses co‑expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague‑Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen‑activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII‑induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII‑induced media hypertrophy compared with that of the control virus (Padventitial α‑smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII‑induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII‑induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation.

  1. The adventitia: Essential role in pulmonary vascular remodeling.

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    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.

  2. Nestin upregulation characterizes vascular remodeling secondary to hypertension in the rat.

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    Tardif, Kim; Hertig, Vanessa; Duquette, Natacha; Villeneuve, Louis; El-Hamamsy, Ismail; Tanguay, Jean-François; Calderone, Angelino

    2015-05-15

    Proliferation and hypertrophy of vascular smooth muscle cells represent hallmark features of vessel remodeling secondary to hypertension. The intermediate filament protein nestin was recently identified in vascular smooth muscle cells and in other cell types directly participated in proliferation. The present study tested the hypothesis that vessel remodeling secondary to hypertension was characterized by nestin upregulation in vascular smooth muscle cells. Two weeks after suprarenal abdominal aorta constriction of adult male Sprague-Dawley rats, elevated mean arterial pressure increased the media area and thickness of the carotid artery and aorta and concomitantly upregulated nestin protein levels. In the normal adult rat carotid artery, nestin immunoreactivity was observed in a subpopulation of vascular smooth muscle cells, and the density significantly increased following suprarenal abdominal aorta constriction. Filamentous nestin was detected in cultured rat carotid artery- and aorta-derived vascular smooth muscle cells and an analogous paradigm observed in human aorta-derived vascular smooth muscle cells. ANG II and EGF treatment of vascular smooth muscle cells stimulated DNA and protein synthesis and increased nestin protein levels. Lentiviral short-hairpin RNA-mediated nestin depletion of carotid artery-derived vascular smooth muscle cells inhibited peptide growth factor-stimulated DNA synthesis, whereas protein synthesis remained intact. These data have demonstrated that vessel remodeling secondary to hypertension was characterized in part by nestin upregulation in vascular smooth muscle cells. The selective role of nestin in peptide growth factor-stimulated DNA synthesis has revealed that the proliferative and hypertrophic responses of vascular smooth muscle cells were mediated by divergent signaling events. Copyright © 2015 the American Physiological Society.

  3. Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica.

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    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

  4. Involvement of the Reck tumor suppressor protein in maternal and embryonic vascular remodeling in mice

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    Kitayama Hitoshi

    2010-08-01

    Full Text Available Abstract Background Developmental angiogenesis proceeds through multiple morphogenetic events including sprouting, intussusception, and pruning. Mice lacking the membrane-anchored metalloproteinase regulator Reck die in utero around embryonic day 10.5 with halted vascular development; however, the mechanisms by which this phenotype arises remain unclear. Results We found that Reck is abundantly expressed in the cells associated with blood vessels undergoing angiogenesis or remodelling in the uteri of pregnant female mice. Some of the Reck-positive vessels show morphological features consistent with non-sprouting angiogenesis. Treatment with a vector expressing a small hairpin RNA against Reck severely disrupts the formation of blood vessels with a compact, round lumen. Similar defects were found in the vasculature of Reck-deficient or Reck conditional knockout embryos. Conclusions Our findings implicate Reck in vascular remodeling, possibly through non-sprouting angiogenesis, in both maternal and embyornic tissues.

  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. Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

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    Cristian R. Astorga

    2018-03-01

    Full Text Available Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN, a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs.Methods: Twelve lambs (Ovis aries gestated and born at highlands (3,600 m were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle and 6 were treated with melatonin (MN, 1 mg.kg−1.d−1 during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations.Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05. This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05 and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05. Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05. Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05.Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia.

  7. Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs

    Science.gov (United States)

    Astorga, Cristian R.; González-Candia, Alejandro; Candia, Alejandro A.; Figueroa, Esteban G.; Cañas, Daniel; Ebensperger, Germán; Reyes, Roberto V.; Llanos, Aníbal J.; Herrera, Emilio A.

    2018-01-01

    Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs. Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg−1.d−1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations. Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05). Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia. PMID:29559926

  8. Longitudinal visualization of vascular occlusion, reperfusion, and remodeling in a zebrafish model of retinal vascular leakage using OCT angiography

    Science.gov (United States)

    Spitz, Kathleen; Bozic, Ivan; Desai, Vineet; Rao, Gopikrishna M.; Pollock, Lana M.; Anand-Apte, Bela; Tao, Yuankai K.

    2017-02-01

    Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are two of the leading causes of blindness and visual impairment in the world. Neovascularization results in severe vision loss in DR and AMD and, thus, there is an unmet need to identify mechanisms of pathogenesis and novel anti-angiogenic therapies. Zebrafish is a leading model organism for studying human disease pathogenesis, and the highly conserved drug activity between zebrafish and humans and their ability to readily absorb small molecules dissolved in water has benefited pharmaceutical discovery. Here, we use optical coherence tomography (OCT) and OCT angiography (OCT-A) to perform noninvasive, in vivo retinal imaging in a zebrafish model of vascular leakage. Zebrafish were treated with diethylaminobenzaldehyde (DEAB) to induce vascular leakage and imaged with OCT and OCT-A at six time points over two weeks: baseline one day before treatment and one, three, six, eight, and ten days post treatment. Longitudinal functional imaging showed significant vascular response immediately after DEAB treatment. Observed vascular changes included partial or complete vascular occlusion immediately after treatment and reperfusion during a two-week period. Increased vascular tortuosity several days post treatment indicated remodeling, and bifurcations and collateral vessel formation were also observed. In addition, significant treatment response variabilities were observed in the contralateral eye of the same animal. Anatomical and functional normalization was observed in most animals by ten days post treatment. These preliminary results motivate potential applications of OCT-A as a tool for studying pathogenesis and therapeutic screening in zebrafish models of retinal vascular disease.

  9. Roselle supplementation prevents nicotine-induced vascular endothelial dysfunction and remodelling in rats.

    Science.gov (United States)

    Si, Lislivia Yiang-Nee; Kamisah, Yusof; Ramalingam, Anand; Lim, Yi Cheng; Budin, Siti Balkis; Zainalabidin, Satirah

    2017-07-01

    Vascular endothelial dysfunction (VED) plays an important role in the initiation of cardiovascular diseases. Roselle, enriched with antioxidants, demonstrates high potential in alleviating hypertension. This study was undertaken to investigate the effects of roselle supplementation of VED and remodelling in a rodent model with prolonged nicotine administration. Male Sprague-Dawley rats (n = 6 per group) were administered with 0.6 mg/kg nicotine for 28 days to induce VED. The rats were given either aqueous roselle (100 mg/kg) or normal saline orally 30 min prior to nicotine injection daily. One additional group of rats served as control. Thoracic aorta was isolated from rats to measure vascular reactivity, vascular remodelling and oxidative stress. Roselle significantly lowered aortic sensitivity to phenylephrine-induced vasoconstriction (Endo-(+) C max = 234.5 ± 3.9%, Endo-(-) C max = 247.6 ± 5.2%) compared with untreated nicotine group (Endo-(+) C max = 264.5 ± 6.9%, Endo-(-) C max = 276.5 ± 6.8%). Roselle also improved aortic response to endothelium-dependent vasodilator, acetylcholine (Endo-(+) R max = 73.2 ± 2.1%, Endo-(-) R max = 26.2 ± 0.8%) compared to nicotine group (Endo-(+) R max = 57.8 ± 1.7%, Endo-(-) R max = 20.9 ± 0.8%). In addition, roselle prevented an increase in intimal media thickness and elastic lamellae proliferation to preserve vascular architecture. Moreover, we also observed a significantly lowered degree of oxidative stress in parallel with increased antioxidant enzymes in aortic tissues of the roselle-treated group. This study demonstrated that roselle prevents VED and remodelling, and as such it has high nutraceutical value as supplement to prevent cardiovascular diseases.

  10. 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.

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

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    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.

  12. 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.

  13. Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats.

    Science.gov (United States)

    Li, Peng; Huang, Pei-Pei; Yang, Yun; Liu, Chi; Lu, Yan; Wang, Fang; Sun, Wei; Kong, Xiang-Qing

    2017-01-01

    Li P, Huang P, Yang Y, Liu C, Lu Y, Wang F, Sun W, Kong X. Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats. J Appl Physiol 122: 121-129, 2017. First published October 14, 2016; doi:10.1152/japplphysiol.01019.2015-Sympathetic activity is enhanced in patients with essential or secondary hypertension, as well as in various hypertensive animal models. Therapeutic targeting of sympathetic activation is considered an effective antihypertensive strategy. We hypothesized that renal sympathetic denervation (RSD) attenuates hypertension and improves vascular remodeling and renal disease in the 2-kidney, 1-clip (2K1C) rat model. Rats underwent 2K1C modeling or sham surgery; then rats underwent RSD or sham surgery 4 wk later, thus resulting in four groups (normotensive-sham, normotensive-RSD, 2K1C-sham, and 2K1C-RSD). Norepinephrine was measured by ELISA. Echocardiography was used to assess heart function. Fibrosis and apoptosis were assessed by Masson and TUNEL staining. Changes in mean arterial blood pressure in response to hexamethonium and plasma norepinephrine levels were used to evaluate basal sympathetic nerve activity. The 2K1C modeling success rate was 86.8%. RSD reversed the elevated systolic blood pressure induced by 2K1C, but had no effect on body weight. Compared with rats in the 2K1C-sham group, rats in the 2K1C-RSD group showed lower left ventricular mass/body weight ratio, interventricular septal thickness in diastole, left ventricular end-systolic diameter, and left ventricular posterior wall thickness in systole, whereas fractional shortening and ejection fraction were higher. Right kidney apoptosis and left kidney hypertrophy were not changed by RSD. Arterial fibrosis was lower in animals in the 2K1C-RSD group compared with those in the 2K1C-sham group. RSD reduced plasma norepinephrine and basal sympathetic activity in rats in the 2K1C-RSD group compared with rats in the 2K1C-sham group. These

  14. 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.

  15. Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress.

    Science.gov (United States)

    Pearson-Leary, J; Eacret, D; Chen, R; Takano, H; Nicholas, B; Bhatnagar, S

    2017-06-27

    During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, we used nonbiased analyses of microRNAs in the ventral hippocampus (vHPC) to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat. In the vHPC of active coping rats, miR-455-3p level was increased, while miR-30e-3p level was increased in the vHPC of passive coping rats. Pathway analyses identified inflammatory and vascular remodeling pathways as enriched by genes targeted by these microRNAs. Utilizing several independent markers for blood vessels, inflammatory processes and neural activity in the vHPC, we found that SL/vulnerable rats exhibit increased neural activity, vascular remodeling and inflammatory processes that include both increased blood-brain barrier permeability and increased number of microglia in the vHPC relative to control and resilient rats. To test the relevance of these changes for the development of the vulnerable phenotype, we used pharmacological approaches to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. Collectively, these results show that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the vHPC. These results suggest that dampening inflammatory processes by administering anti-inflammatory agents reduces

  16. Arterial grafts exhibiting unprecedented cellular infiltration and remodeling in vivo: the role of cells in the vascular wall.

    Science.gov (United States)

    Row, Sindhu; Peng, Haofan; Schlaich, Evan M; Koenigsknecht, Carmon; Andreadis, Stelios T; Swartz, Daniel D

    2015-05-01

    To engineer and implant vascular grafts in the arterial circulation of a pre-clinical animal model and assess the role of donor medial cells in graft remodeling and function. Vascular grafts were engineered using Small Intestinal Submucosa (SIS)-fibrin hybrid scaffold and implanted interpositionally into the arterial circulation of an ovine model. We sought to demonstrate implantability of SIS-Fibrin based grafts; examine the remodeling; and determine whether the presence of vascular cells in the medial wall was necessary for cellular infiltration from the host and successful remodeling of the implants. We observed no occlusions or anastomotic complications in 18 animals that received these grafts. Notably, the grafts exhibited unprecedented levels of host cell infiltration that was not limited to the anastomotic sites but occurred through the lumen as well as the extramural side, leading to uniform cell distribution. Incoming cells remodeled the extracellular matrix and matured into functional smooth muscle cells as evidenced by expression of myogenic markers and development of vascular reactivity. Interestingly, tracking the donor cells revealed that their presence was beneficial but not necessary for successful grafting. Indeed, the proliferation rate and number of donor cells decreased over time as the vascular wall was dominated by host cells leading to significant remodeling and development of contractile function. These results demonstrate that SIS-Fibrin grafts can be successfully implanted into the arterial circulation of a clinically relevant animal model, improve our understanding of vascular graft remodeling and raise the possibility of engineering mural cell-free arterial grafts. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    OpenAIRE

    van Loon, Rosa Laura E; Bartelds, Beatrijs; Wagener, Frank A D T G; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W C; Takens, Janny; Berger, Rolf M F

    2015-01-01

    BACKGROUND: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1). METHODS: Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the pre...

  18. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    OpenAIRE

    van Loon, Rosa Laura E.; Bartelds, Beatrijs; Wagener, Frank A. D. T. G.; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W. C.; Takens, Janny; Berger, Rolf M. F.

    2015-01-01

    Background Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1). Methods Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO i...

  19. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage.

    Science.gov (United States)

    Frid, Maria G; Brunetti, Jacqueline A; Burke, Danielle L; Carpenter, Todd C; Davie, Neil J; Reeves, John T; Roedersheimer, Mark T; van Rooijen, Nico; Stenmark, Kurt R

    2006-02-01

    Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.

  20. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

    Science.gov (United States)

    Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

    2015-06-01

    The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.

  1. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.

    Science.gov (United States)

    Schwabl, Philipp; Hambruch, Eva; Seeland, Berit A; Hayden, Hubert; Wagner, Michael; Garnys, Lukas; Strobel, Bastian; Schubert, Tim-Lukas; Riedl, Florian; Mitteregger, Dieter; Burnet, Michael; Starlinger, Patrick; Oberhuber, Georg; Deuschle, Ulrich; Rohr-Udilova, Nataliya; Podesser, Bruno K; Peck-Radosavljevic, Markus; Reiberger, Thomas; Kremoser, Claus; Trauner, Michael

    2017-04-01

    Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl 4 , 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl 4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl 4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; pportal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. Copyright

  2. Krypton laser photocoagulation induces retinal vascular remodeling rather than choroidal neovascularization.

    Science.gov (United States)

    Behar-Cohen, F; Benezra, D; Soubrane, G; Jonet, L; Jeanny, J C

    2006-08-01

    The purpose of this study is to analyze the retina and choroid response following krypton laser photocoagulation. Ninety-two C57BL6/Sev129 and 32 C57BL/6J, 5-6-week-old mice received one single krypton (630 nm) laser lesion: 50 microm, 0.05 s, 400 mW. On the following day, every day thereafter for 1 week and every 2-3 days for the following 3 weeks, serial sections throughout the lesion were systematically collected and studied. Immunohistology using specific markers or antibodies for glial fibrillary acidic protein (GFAP) (astrocytes, glia and Muller's cells), von Willebrand (vW) (vascular endothelial cells), TUNEL (cells undergoing caspase dependent apoptosis), PCNA (proliferating cell nuclear antigen) p36, CD4 and F4/80 (infiltrating inflammatory and T cells), DAPI (cell nuclei) and routine histology were carried out. Laser confocal microscopy was also performed on flat mounts. Temporal and spatial observations of the created photocoagulation lesions demonstrate that, after a few hours, activated glial cells within the retinal path of the laser beam express GFAP. After 48 h, GFAP-positive staining was also detected within the choroid lesion center. "Movement" of this GFAP-positive expression towards the lasered choroid was preceded by a well-demarcated and localized apoptosis of the retina outer nuclear layer cells within the laser beam path. Later, death of retinal outer nuclear cells and layer thinning at this site was followed by evagination of the inner nuclear retinal layer. Funneling of the entire inner nuclear and the thinned outer nuclear layers into the choroid lesion center was accompanied by "dragging" of the retinal capillaries. Thus, from days 10 to 14 after krypton laser photocoagulation onward, well-formed blood capillaries (of retinal origin) were observed within the lesion. Only a few of the vW-positive capillary endothelial cells stained also for PCNA p36. In the choroid, dilatation of the vascular bed occurred at the vicinity of the

  3. Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

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    Weissmann Norbert

    2005-11-01

    Full Text Available Abstract Background The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH in rats. Methods CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii the anti-remodeling effect of long-term inhalation of tolafentrine (iii the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. Results Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks, cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers, after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery

  4. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

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    Karki, Rajendra; Kim, Seong-Bin; Kim, Dong-Wook

    2013-01-01

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  5. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

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    Karki, Rajendra [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City (United States); Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of); Kim, Seong-Bin [Jeollanamdo Development Institute for Korean Traditional Medicine, Jangheung gun, Jeollanamdo (Korea, Republic of); Kim, Dong-Wook, E-mail: dbkim@mokpo.ac.kr [Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of)

    2013-12-10

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  6. Vascular Wall-Resident Multipotent Stem Cells of Mesenchymal Nature within the Process of Vascular Remodeling: Cellular Basis, Clinical Relevance, and Implications for Stem Cell Therapy.

    Science.gov (United States)

    Klein, Diana

    2016-01-01

    Until some years ago, the bone marrow and the endothelial cell compartment lining the vessel lumen (subendothelial space) were thought to be the only sources providing vascular progenitor cells. Now, the vessel wall, in particular, the vascular adventitia, has been established as a niche for different types of stem and progenitor cells with the capacity to differentiate into both vascular and nonvascular cells. Herein, vascular wall-resident multipotent stem cells of mesenchymal nature (VW-MPSCs) have gained importance because of their large range of differentiation in combination with their distribution throughout the postnatal organism which is related to their existence in the adventitial niche, respectively. In general, mesenchymal stem cells, also designated as mesenchymal stromal cells (MSCs), contribute to the maintenance of organ integrity by their ability to replace defunct cells or secrete cytokines locally and thus support repair and healing processes of the affected tissues. This review will focus on the central role of VW-MPSCs within vascular reconstructing processes (vascular remodeling) which are absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. Further, a particular advantage for the therapeutic application of VW-MPSCs for improving vascular function or preventing vascular damage will be discussed.

  7. Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia

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    Laurie G. Sherlock

    2018-03-01

    Full Text Available Background: A naturally occurring single nucleotide polymorphism (SNP, (R213G, in extracellular superoxide dismutase (SOD3, decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Methods: Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH was assessed by right ventricular hypertrophy (RVH. Lung protein expression for superoxide dismutase (SOD isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2, endothelial nitric oxide synthase (eNOS and guanosine triphosphate cyclohydrolase-1 (GTPCH-1 was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. Results: In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. Conclusion: R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and

  8. Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin

    Science.gov (United States)

    Boroujerdi, Amin; Welser-Alves, Jennifer V.; Milner, Richard

    2013-01-01

    Alterations in vascular structure and function are a central component of demyelinating disease. In addition to blood-brain barrier (BBB) breakdown, which occurs early in the course of disease, recent studies have described angiogenic remodeling, both in multiple sclerosis tissue and in the mouse demyelinating model, experimental autoimmune encephalomyelitis (EAE). As the precise timing of vascular remodeling in demyelinating disease has yet to be fully defined, the purpose of the current study was to define the time-course of these events in the MOG35-55 EAE model. Quantification of endothelial cell proliferation and vessel density revealed that a large part of angiogenic remodeling in cervical spinal cord white matter occurs during the pre-symptomatic phase of EAE. At the height of vascular remodeling, blood vessels in the cervical spinal cord showed strong transient upregulation of fibronectin and the α5β1 integrin. In vitro experiments revealed that α5 integrin inhibition reduced brain endothelial cell proliferation under inflammatory conditions. Interestingly, loss of vascular integrity was evident in all vessels during the first 4–7 days post-immunization, but after 14 days, was localized predominantly to venules. Taken together, our data demonstrate that extensive vascular remodeling occurs during the pre-symptomatic phase of EAE and point to a potential role for the fibronectin-α5β1 integrin interaction in promoting vascular remodeling during demyelinating disease. PMID:24056042

  9. Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension.

    Science.gov (United States)

    Qingyan, Zhao; Xuejun, Jiang; Yanhong, Tang; Zixuan, Dai; Xiaozhan, Wang; Xule, Wang; Zongwen, Guo; Wei, Hu; Shengbo, Yu; Congxin, Huang

    2015-07-01

    Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system is closely associated with pulmonary arterial hypertension. We hypothesized that renal denervation decreases renin-angiotensin-aldosterone activity and inhibits the progression of pulmonary arterial hypertension. Twenty-two beagles were randomized into 3 groups. The dogs' pulmonary dynamics were measured before and 8 weeks after injection of 0.1mL/kg dimethylformamide (control dogs) or 2mg/kg dehydromonocrotaline (pulmonary arterial hypertension and pulmonary arterial hypertension + renal denervation dogs). Eight weeks after injection, neurohormone levels and pulmonary tissue morphology were measured. Levels of plasma angiotensin II and endothelin-1 were significantly increased after 8 weeks in the pulmonary arterial hypertension dogs and were higher in the lung tissues of these dogs than in those of the control and renal denervation dogs (mean [standard deviation] angiotensin II: 65 [9.8] vs 38 [6.7], 46 [8.1]; endothelin-1: 96 [10.3] vs 54 [6.2], 67 [9.4]; P < .01). Dehydromonocrotaline increased the mean pulmonary arterial pressure (16 [3.4] mmHg vs 33 [7.3] mmHg; P < .01), and renal denervation prevented this increase. Pulmonary smooth muscle cell proliferation was higher in the pulmonary arterial hypertension dogs than in the control and pulmonary arterial hypertension + renal denervation dogs. Renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental pulmonary arterial hypertension. The effect of renal denervation may contribute to decreased neurohormone levels. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  10. Kinetics of cardiac and vascular remodeling by spontaneously hypertensive rats after discontinuation of long-term captopril treatment

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    W.A. Rocha

    2010-04-01

    Full Text Available Angiotensin-converting enzyme inhibitors reduce blood pressure and attenuate cardiac and vascular remodeling in hypertension. However, the kinetics of remodeling after discontinuation of the long-term use of these drugs are unknown. Our objective was to investigate the temporal changes occurring in blood pressure and vascular structure of spontaneously hypertensive rats (SHR. Captopril treatment was started in the pre-hypertensive state. Rats (4 weeks were assigned to three groups: SHR-Cap (N = 51 treated with captopril (1 g/L in drinking water from the 4th to the 14th week; SHR-C (N = 48 untreated SHR; Wistar (N = 47 control rats. Subgroups of animals were studied at 2, 4, and 8 weeks after discontinuation of captopril. Direct blood pressure was recorded in freely moving animals after femoral artery catheterism. The animals were then killed to determine left ventricular hypertrophy (LVH and the aorta fixed at the same pressure measured in vivo. Captopril prevented hypertension (105 ± 3 vs 136 ± 5 mmHg, LVH (2.17 ± 0.05 vs 2.97 ± 0.14 mg/g body weight and the increase in cross-sectional area to luminal area ratio of the aorta (0.21 ± 0.01 vs 0.26 ± 0.02 μm² (SHR-Cap vs SHR-C. However, these parameters increased progressively after discontinuation of captopril (22nd week: 141 ± 2 mmHg, 2.50 ± 0.06 mg/g, 0.27 ± 0.02 μm². Prevention of the development of hypertension in SHR by using captopril during the prehypertensive period prevents the development of cardiac and vascular remodeling. Recovery of these processes follows the kinetic of hypertension development after discontinuation of captopril.

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

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    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

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

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    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

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

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    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.

  14. Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.

    Science.gov (United States)

    Tong, Xin-Kang; Nicolakakis, Nektaria; Kocharyan, Ara; Hamel, Edith

    2005-11-30

    The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.

  15. Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an α5β1 integrin-mediated mechanism.

    Science.gov (United States)

    Halder, Sebok K; Kant, Ravi; Milner, Richard

    2018-05-01

    Spinal cord injury (SCI) leads to rapid destruction of neuronal tissue, resulting in devastating motor and sensory deficits. This is exacerbated by damage to spinal cord blood vessels and loss of vascular integrity. Thus, approaches that protect existing blood vessels or stimulate the growth of new blood vessels might present a novel approach to minimize loss or promote regeneration of spinal cord tissue following SCI. In light of the remarkable power of chronic mild hypoxia (CMH) to stimulate vascular remodeling in the brain, the goal of this study was to examine how CMH (8% O 2 for up to 7 days) affects blood vessel remodeling in the spinal cord. We found that CMH promoted the following: (1) endothelial proliferation and increased vascularity as a result of angiogenesis and arteriogenesis, (2) increased vascular expression of the angiogenic extracellular matrix protein fibronectin as well as concomitant increases in endothelial expression of the fibronectin receptor α5β1 integrin, (3) strongly upregulated endothelial expression of the tight junction proteins claudin-5, ZO-1 and occludin and (4) astrocyte activation. Of note, the vascular remodeling changes induced by CMH were more extensive in white matter. Interestingly, hypoxic-induced vascular remodeling in spinal cord blood vessels was markedly attenuated in mice lacking endothelial α5 integrin expression (α5-EC-KO mice). Taken together, these studies demonstrate the considerable remodeling potential of spinal cord blood vessels and highlight an important angiogenic role for the α5β1 integrin in promoting endothelial proliferation. They also imply that stimulation of the α5β1 integrin or controlled use of mild hypoxia might provide new approaches for promoting angiogenesis and improving vascular integrity in spinal cord blood vessels.

  16. A phosphatidylinositol 3-kinase inhibitor strongly suppressed pulmonary vascular remodeling of allergic vasculitis in a murine model.

    Science.gov (United States)

    Oikawa, Yuka; Sasaki, Nobuhito; Niisato, Miyuki; Nakamura, Yutaka; Yamauchi, Kohei

    2016-04-01

    We investigated the effects of pan-class I PI3K inhibitor, ZSTK474 on vascular remodeling using a murine model of allergic vasculitis with eosinophil infiltration. C57BL/6 mice were sensitized with OVA. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice were administered ZSTK474 (30 mg/kg, p.o. daily) in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of IL-4, IL-5, IL-13 and TGF-βin BAL fluid were measured. The total cell numbers and eosinophil numbers in BALF were greatly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The numbers of total white blood cells and eosinophils in the peripheral blood were significantly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The concentrations of IL-4, IL-5, and IL-13 in BAL fluids were also reduced significantly on the 3rd day in the ZSTK474-treated group. The concentrations of TGF-β in BAL fluids were also reduced significantly on the 3rd and 7th day in the ZSTK474-treated group. The pathological scores reduced significantly in the ZSTK474-treated group compared to the control group. The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis.

  17. Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension.

    Science.gov (United States)

    Dai, Zhiyu; Zhu, Maggie M; Peng, Yi; Jin, Hua; Machireddy, Narsa; Qian, Zhijian; Zhang, Xianming; Zhao, You-Yang

    2018-04-17

    Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in PH development. SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of idiopathic PAH patients and 4 discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1 and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation and PH. Accordingly, pharmacological inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of IPAH.

  18. 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.

  19. From here to there, progenitor cells and stem cells are everywhere in lung vascular remodeling

    Directory of Open Access Journals (Sweden)

    Rebecca L. Heise

    2016-08-01

    Full Text Available The field of stem cell biology, cell therapy and regenerative medicine has expanded almost exponentially in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD, chronic obstructive pulmonary disease (COPD, idiopathic pulmonary fibrosis (IPF or pulmonary arterial hypertension (PAH. Extensive research activity is exploring lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field.

  20. Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    da Silva Gonçalves Bós, Denielli; Van Der Bruggen, Cathelijne E E; Kurakula, Kondababu; Sun, Xiao-Qing; Casali, Karina R; Casali, Adenauer G; Rol, Nina; Szulcek, Robert; Dos Remedios, Cris; Guignabert, Christophe; Tu, Ly; Dorfmüller, Peter; Humbert, Marc; Wijnker, Paul J M; Kuster, Diederik W D; van der Velden, Jolanda; Goumans, Marie-José; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; de Man, Frances S; Handoko, M Louis

    2018-02-27

    PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH. © 2017 American Heart Association, Inc.

  1. Luminally-polarized mural and vascular remodeling in ileal strictures of Crohn's Disease.

    Science.gov (United States)

    Zhang, Xiaofei; Ko, Huaibin Mabel; Torres, Joana; Panchal, Hinaben J; Cai, Zhenjian; Wagner, Mathilde; Sands, Bruce E; Colombel, Jean-Frederic; Cho, Judy; Taouli, Bachir; Harpaz, Noam

    2018-03-16

    Intestinal stricture, a major complication of Crohn's disease (CD), results from fibromuscular remodeling and expansion of the intestinal wall. The corresponding microanatomical alterations have not been fully described, hindering progress toward understanding their pathogenesis and devising appropriate treatments. We used tissue-specific staining and quantitative digital histomorphometry for this purpose. Serial histological sections from 37 surgically-resected ileal strictures and adjacent non-strictured controls from patients with CD were evaluated after staining for smooth muscle actin, collagen (Sirius red) and collagen types I, III and V. Overall mural thickening in strictures was increased 2.4±0.3-fold compared with non-strictured regions of the same specimens. The muscular layer most altered was the muscularis mucosae (MM). Compared with the inner and outer layers of the MP which were expanded 2.1±0.2- and 1.4±0.1-fold, respectively, the MM was expanded 22.1±3.6-fold, reflecting the combined effects of architectural disarray, an 11.6±1.4-fold increase smooth muscle content, and elaboration of pericellular type V collagen. In contrast, the architecture of the MP was preserved and pericellular collagen was virtually absent; rather, fibrosis in this layer was limited to expansion of the intramuscular septa by collagen types I and III. The muscular arteries and veins within the strictured submucosa frequently exhibited eccentric, luminally-oriented adventitial mantles comprising hyperplastic myocytes and extracellular type V collagen. We conclude that the fibromuscular remodeling which results in CD-associated ileal strictures predominantly involves the MM and submucosal vasculature in a luminally-polarized fashion and suggests that mucosal-based factors may contribute to stricture pathogenesis. Copyright © 2018. Published by Elsevier Inc.

  2. Skeletal Muscle Regeneration, Repair and Remodelling in Aging: The Importance of Muscle Stem Cells and Vascularization.

    Science.gov (United States)

    Joanisse, Sophie; Nederveen, Joshua P; Snijders, Tim; McKay, Bryon R; Parise, Gianni

    2017-01-01

    Sarcopenia is the age-related loss of skeletal muscle mass and strength. Ultimately, sarcopenia results in the loss of independence, which imposes a large financial burden on healthcare systems worldwide. A critical facet of sarcopenia is the diminished ability for aged muscle to regenerate, repair and remodel. Over the years, research has focused on elucidating underlying mechanisms of sarcopenia and the impaired ability of muscle to respond to stimuli with aging. Muscle-specific stem cells, termed satellite cells (SC), play an important role in maintaining muscle health throughout the lifespan. It is well established that SC are essential in skeletal muscle regeneration, and it has been hypothesized that a reduction and/or dysregulation of the SC pool, may contribute to accelerated loss of skeletal muscle mass that is observed with advancing age. The preservation of skeletal muscle tissue and its ability to respond to stimuli may be impacted by reduced SC content and impaired function observed with aging. Aging is also associated with a reduction in capillarization of skeletal muscle. We have recently demonstrated that the distance between type II fibre-associated SC and capillaries is greater in older compared to younger adults. The greater distance between SC and capillaries in older adults may contribute to the dysregulation in SC activation ultimately impairing muscle's ability to remodel and, in extreme circumstances, regenerate. This viewpoint will highlight the importance of optimal SC activation in addition to skeletal muscle capillarization to maximize the regenerative potential of skeletal muscle in older adults. © 2016 S. Karger AG, Basel.

  3. Effect of gender on training-induced vascular remodeling in SHR

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    S.L. Amaral

    2011-09-01

    Full Text Available There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR. Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density were similar in male and female SHR, supporting a similar hyperemic response to exercise.

  4. Effect of gender on training-induced vascular remodeling in SHR.

    Science.gov (United States)

    Amaral, S L; Michelini, L C

    2011-09-01

    There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

  5. A Potential Role for Exosomal TCTP Export in Vascular Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Ferrer, Elisabet; Dunmore, Benjamin J; Hassan, Dhiya; Ormiston, Mark L; Moore, Stephen; Deighton, John; Long, Lu; Yang, Xu Dong; Stewart, Duncan J; Morrell, Nicholas W

    2018-04-20

    Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and resistance to apoptosis of pulmonary vascular cells. Increased expression of translationally controlled tumor protein (TCTP), a pro-survival and anti-apoptotic mediator, has recently been demonstrated in patients with hereditary PAH (HPAH) although its role in the pathobiology of PAH remains unclear. Silencing of TCTP in blood outgrowth endothelial cells (BOECs) isolated from control subjects led to significant changes in morphology, cytoskeletal organization, increased apoptosis and decreased directionality during migration. As TCTP is also localized in extracellular vesicles (EVs), we isolated BOEC-derived EVs (exosomes and microparticles) by sequential ultracentrifugation. BOECs isolated from patients harboring BMPR2 mutations released more exosomes than controls in pro-apoptotic conditions. Furthermore, TCTP protein expression was significantly higher in exosomes compared to microparticles, indicating that TCTP is mainly exported via exosomes. Co-culture assays demonstrated that exosomes transferred TCTP from endothelial cells (ECs) to pulmonary artery smooth muscle cells (PASMCs) suggesting a role for endothelial-derived TCTP in conferring proliferation and apoptotic resistance. In an experimental model of PAH, rats treated with monocrotaline demonstrated increased concentrations of TCTP in the lung and plasma. Consistent with this finding, we observed increased circulating TCTP levels in patients with IPAH compared with controls. Therefore, our data suggests an important role for TCTP in regulating the critical vascular cell phenotypes implicated in the pathobiology of PAH. In addition, this research implicates TCTP as a potential biomarker for the onset and development of PAH.

  6. Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart.

    Science.gov (United States)

    Abdul-Ghani, Mohammad; Suen, Colin; Jiang, Baohua; Deng, Yupu; Weldrick, Jonathan J; Putinski, Charis; Brunette, Steve; Fernando, Pasan; Lee, Tom T; Flynn, Peter; Leenen, Frans H H; Burgon, Patrick G; Stewart, Duncan J; Megeney, Lynn A

    2017-10-01

    The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial (physiologic hypertrophy). Physiologic hypertrophy improves cardiac performance in both healthy and diseased individuals, yet the mechanisms that propagate this favorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.

  7. Involvement of Inflammation and Adverse Vascular Remodelling in the Blood Pressure Raising Effect of Repeatedly Heated Palm Oil in Rats

    Directory of Open Access Journals (Sweden)

    Chun-Yi Ng

    2012-01-01

    Full Text Available Oil thermoxidation during deep frying generates harmful oxidative free radicals that induce inflammation and increase the risk of hypertension. This study aimed to investigate the effect of repeatedly heated palm oil on blood pressure, aortic morphometry, and vascular cell adhesion molecule-1 (VCAM-1 expression in rats. Male Sprague-Dawley rats were divided into five groups: control, fresh palm oil (FPO, one-time-heated palm oil (1HPO, five-time-heated palm oil (5HPO, or ten-time-heated palm oil (10HPO. Feeding duration was six months. Blood pressure was measured at baseline and monthly using tail-cuff method. After six months, the rats were sacrificed and the aortic arches were dissected for morphometric and immunohistochemical analyses. FPO group showed significantly lower blood pressure than all other groups. Blood pressure was increased significantly in 5HPO and 10HPO groups. The aortae of 5HPO and 10HPO groups showed significantly increased thickness and area of intima-media, circumferential wall tension, and VCAM-1 than other groups. Elastic lamellae were disorganised and fragmented in 5HPO- and 10HPO-treated rats. VCAM-1 expression showed a significant positive correlation with blood pressure. In conclusion, prolonged consumption of repeatedly heated palm oil causes blood pressure elevation, adverse remodelling, and increased VCAM-1, which suggests a possible involvement of inflammation.

  8. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

    Directory of Open Access Journals (Sweden)

    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  9. Time and flow-dependent changes in the p27(kip1) gene network drive maladaptive vascular remodeling.

    Science.gov (United States)

    DeSart, Kenneth M; Butler, Khayree; O'Malley, Kerri A; Jiang, Zhihua; Berceli, Scott A

    2015-11-01

    divergent patterns of vein graft remodeling. Associated with the dramatic increase in neointimal expansion observed in low-flow vs high-flow grafts is a subset of differentially expressed p27(kip1)-associated genes that correlate with critical stages in the adaptive response. These represent potential biologic targets whose activity may be altered to augment maladaptive vascular remodeling. Published by Elsevier Inc.

  10. 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)

  11. Expression of PDGF-beta receptor in broilers with pulmonary hypertension induced by cold temperature and its association with pulmonary vascular remodeling.

    Science.gov (United States)

    Li, Jin-Chun; Pan, Jia-Qiang; Huang, Guo-Qing; Tan, Xun; Sun, Wei-Dong; Liu, Yan-Juan; Wang, Xiao-Long

    2010-02-01

    The purpose of the present study was to characterize the relationship between platelet-derived growth factor beta receptor (PDGF-beta receptor) expression and pulmonary vascular remodeling found in broilers subjected to cold temperature beginning at 14 days of age. One hundred and sixty-one-day-old mixed-sex Avian-2000 commercial broilers were randomly divided into a normal temperature group (control) and a cold temperature group (cold). All the birds were brooded in normal temperature up to day 14, with the lighting schedule at 24 h per day. Starting at day 14, birds in the cold group were moved to a pen in the cold house and subjected to low temperature, while birds in the control group were still brooded at normal temperature. On days 14, 23, 30, 37 and 44, the right/total ventricle weight ratio (RV/TV), packed cell volume (PCV), the vessel wall area to vessel total area ratio (WA/TA), mean media thickness in pulmonary arterioles (mMTPA) and the expression of PDGF-beta receptor in pulmonary arterioles were measured, respectively. Cumulative pulmonary hypertension syndrome (PHS) morbidity was recorded in each group. Cool ambient temperature increased PHS morbidity of broilers. The values of WA/TA and mMTPA were also increased significantly compared with control group. PCV values in the cold temperature group were elevated from days 30 to 44, and RV/TV ratios were increased on days 37 and 44. Cold exposure enhanced PDGF-beta receptor expression in pulmonary arterioles, and the PDGF-beta receptor expression was significantly correlated with pulmonary vascular remodeling that was dedicated by increased WA/TA and mMTPA. The results indicated that PDGF-beta and its receptor were involved in the underlying mechanisms of pulmonary vascular remodeling in pulmonary hypertensive broilers. Copyright 2009 Elsevier Ltd. All rights reserved.

  12. 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

  13. Rice bran protein hydrolysates reduce arterial stiffening, vascular remodeling and oxidative stress in rats fed a high-carbohydrate and high-fat diet.

    Science.gov (United States)

    Senaphan, Ketmanee; Sangartit, Weerapon; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Pannangpetch, Patchareewan; Thawornchinsombut, Supawan; Greenwald, Stephen E; Kukongviriyapan, Upa

    2018-02-01

    Rice bran protein hydrolysates (RBPH) contain highly nutritional proteins and antioxidant compounds which show benefits against metabolic syndrome (MetS). Increased arterial stiffness and the components of MetS have been shown to be associated with an increased risk of cardiovascular disease. This study aimed to investigate whether RBPH could alleviate the metabolic disorders, arterial stiffening, vascular remodeling, and oxidative stress in rats fed a high-carbohydrate and high-fat (HCHF) diet. Male Sprague-Dawley rats were fed either a standard chow and tap water or a HCHF diet and 15 % fructose solution for 16 weeks. HCHF rats were treated orally with RBPH (250 or 500 mg/kg/day) for the final 6 weeks of the experimental period. Rats fed with HCHF diet had hyperglycemia, insulin resistance, dyslipidemia, hypertension, increased aortic pulse wave velocity, aortic wall hypertrophy and vascular remodeling with increased MMP-2 and MMP-9 expression. RBPH supplementation significantly alleviated these alterations (P stress was also alleviated after RBPH treatment by decreasing plasma malondialdehyde, reducing superoxide production and suppressing p47 phox NADPH oxidase expression in the vascular tissues of HCHF rats. RBPH increased plasma nitrate/nitrite level and up-regulated eNOS expression in the aortas of HCHF-diet-fed rats, indicating that RBPH increased NO production. RBPH mitigate the deleterious effects of HCHF through potential mechanisms involving enhanced NO bioavailability, anti-ACE, anti-inflammatory and antioxidant properties. RBPH could be used as dietary supplements to minimize oxidative stress and vascular alterations triggered by MetS.

  14. Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

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    M. Klein

    2008-06-01

    Full Text Available Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o. reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2. After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM. Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway.

  15. Inhibiting trophoblast PAR-1 overexpression suppresses sFlt-1-induced anti-angiogenesis and abnormal vascular remodeling: a possible therapeutic approach for preeclampsia.

    Science.gov (United States)

    Zhao, Yin; Zheng, YanFang; Liu, XiaoXia; Luo, QingQing; Wu, Di; Liu, XiaoPing; Zou, Li

    2018-03-01

    Is it possible to improve vascular remodeling by inhibiting the excessive expression of protease-activated receptor 1 (PAR-1) in trophoblast of abnormal placenta? Inhibition of trophoblast PAR-1 overexpression may promote placental angiogenesis and vascular remodeling, offering an alternative therapeutic approach for preeclampsia. PAR-1 is high-affinity receptor of thrombin. Thrombin increases sFlt-1 secretion in trophoblast via the activation of PAR-1. It is reported that the expression of both thrombin and PAR-1 expression are increased in placentas of preeclampsia patients compared with normal placentas. Trophoblast cells were transfected with PAR-1 short hairpin RNA (shRNA) or PAR-1 overexpression plasmids in vitro. Tube formation assays and a villus-decidua co-culture system were used to study the effect of PAR-1 inhibition on placental angiogenesis and vascular remodeling, respectively. Placentas from rats with preeclampsia were transfected with PAR-1 shRNA to confirm the effect of inhibiting PAR-1 overexpression in placenta. The trophoblast cell line HTR-8/SVneo was transfected with PAR-1 shRNA or PAR-1 overexpression plasmids. After 48 h, supernatant was collected and the level of sFlt-1 secretion was measured by ELISA. Human umbilical cord epithelial cells and a villus-decidua co-culture system were treated with conditioned media to study the effect of PAR-1 inhibition on tube formation and villi vascular remodeling. A preeclampsia rat model was established by intraperitoneal injection of L-NAME. Plasmids were injected into the placenta of the preeclampsia rats and systolic blood pressure was measured on Days 15 and 19. The effect of different treatments was evaluated by proteinuria, placental weights, fetal weights and fetal numbers in study and control groups. The level of serum sFlt-1 in rats with preeclampsia was also measured. Changes in the placenta microvessels were studied by histopathological staining. PAR-1 shRNA inhibited PAR-1 expression and

  16. Hindlimb Suspension as a Model to Study Ophthalmic Complications in Microgravity Status Report: Optimization of Rat Retina Flat Mounts Staining to Study Vascular Remodeling

    Science.gov (United States)

    Theriot, Corey A.; Zanello, Susana B.

    2014-01-01

    Preliminary data from a prior tissue-sharing experiment has suggested that early growth response protein-1 (Egr1), a transcription factor involved in various stress responses in the vasculature, is induced in the rat retina after 14 days of hindlimb suspension (HS) and may be evidence that mechanical stress is occurring secondary to the cephalad fluid shift. This mechanical stress could cause changes in oxygenation of the retina, and the subsequent ischemia- or inflammation-driven hypoxia may lead to microvascular remodeling. This microvascular remodeling process can be studied using image analysis of retinal vessels and can be then be quantified by the VESsel GENeration Analysis (VESGEN) software, a computational tool that quantifies remodeling patterns of branching vascular trees and capillary or vasculogenic networks. Our project investigates whether rodent HS is a valid model to study the effects of simulated-weightlessness on ocular structures and their relationship with intracranial pressure (ICP). One of the hypotheses to be tested is that HS-induced cephalad fluid shift is accompanied by vascular engorgement that produces changes in retinal oxygenation, leading to oxidative stress, hypoxia, microvascular remodeling, and cellular degeneration. We have optimized the procedure to obtain flat mounts of rat retina, staining of the endothelial lining in vasculature and acquisition of high quality images suitable for VESGEN analysis. Briefly, eyes were fixed in 4% paraformaldehyde for 24 hours and retinas were detached and then mounted flat on microscope slides. The microvascular staining was done with endothelial cell-specific isolectin binding, coupled to Alexa-488 fluorophore. Image acquisition at low magnification and high resolution was performed using a new Leica SP8 confocal microscope in a tile pattern across the X,Y plane and multiple sections along the Z-axis. This new confocal microscope has the added capability of dye separation using the Linear

  17. 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

  18. TLR accessory molecule RP105 (CD180 is involved in post-interventional vascular remodeling and soluble RP105 modulates neointima formation.

    Directory of Open Access Journals (Sweden)

    Jacco C Karper

    Full Text Available BACKGROUND: RP105 (CD180 is TLR4 homologue lacking the intracellular TLR4 signaling domain and acts a TLR accessory molecule and physiological inhibitor of TLR4-signaling. The role of RP105 in vascular remodeling, in particular post-interventional remodeling is unknown. METHODS AND RESULTS: TLR4 and RP105 are expressed on vascular smooth muscle cells (VSMC as well as in the media of murine femoral artery segments as detected by qPCR and immunohistochemistry. Furthermore, the response to the TLR4 ligand LPS was stronger in VSMC from RP105(-/- mice resulting in a higher proliferation rate. In RP105(-/- mice femoral artery cuff placement resulted in an increase in neointima formation as compared to WT mice (4982 ± 974 µm(2 vs.1947 ± 278 µm(2,p = 0.0014. Local LPS application augmented neointima formation in both groups, but in RP105(-/- mice this effect was more pronounced (10316±1243 µm(2 vs.4208 ± 555 µm(2,p = 0.0002, suggesting a functional role for RP105. For additional functional studies, the extracellular domain of murine RP105 was expressed with or without its adaptor protein MD1 and purified. SEC-MALSanalysis showed a functional 2∶2 homodimer formation of the RP105-MD1 complex. This protein complex was able to block the TLR4 response in whole blood ex-vivo. In vivo gene transfer of plasmid vectors encoding the extracellular part of RP105 and its adaptor protein MD1 were performed to initiate a stable endogenous soluble protein production. Expression of soluble RP105-MD1 resulted in a significant reduction in neointima formation in hypercholesterolemic mice (2500 ± 573 vs.6581 ± 1894 µm(2,p<0.05, whereas expression of the single factors RP105 or MD1 had no effect. CONCLUSION: RP105 is a potent inhibitor of post-interventional neointima formation.

  19. Upregulation of Klotho potentially inhibits pulmonary vascular remodeling by blocking the activation of the Wnt signaling pathway in rats with PM2.5-induced pulmonary arterial hypertension.

    Science.gov (United States)

    Cong, Lu-Hong; Du, Shi-Yu; Wu, Yi-Na; Liu, Ying; Li, Tao; Wang, Hui; Li, Gang; Duan, Jun

    2018-01-30

    We evaluated the effects of Klotho on pulmonary vascular remodeling and cell proliferation and apoptosis in rat models with PM2.5-induced pulmonary arterial hypertension (PAH) via the Wnt signaling pathway. After establishing rat models of PM2.5-induced PAH, these Sprague-Dawley male rats were randomized into control and model groups. Cells extracted from the model rats were sub-categorized into different groups. Activation of Wnt/β-catenin signaling transcription factor was detected by a TOPFlash/FOPFlash assay. A serial of experiment was conducted to identify the mechanism of Klotho on PHA via the Wnt signaling pathway. VEGF levels and PaCO 2 content were higher in the model group, while PaO 2, NO 2 - /NO 3 - content and Klotho level was lower compared to the control group. In comparison to the control group, the model group had decreased Klotho and Bax levels, and elevated Wnt-1, β-catenin, bcl-2, survivin, and PCNA expression, VEGF, IL-6, TNF-α, TNF-β1, and bFGF levels, as well as the percentage of pulmonary artery ring contraction. The Klotho vector, DKK-1 and DKK-1 + Klotho vector groups exhibited reduced cell proliferation, luciferase activity, and the expression of Wnt-1, β-catenin, bcl-2, survivin, and PCNA, as well as shortened S phase compared with the blank and NC groups. Compared with the Klotho vector and DKK-1 groups, the DKK-1 + Klotho vector groups had reduced cell proliferation, luciferase activity, and the expression of Wnt-1, β-catenin, bcl-2, survivin, and PCNA, as well as a shortened S phase. Conclusively, Klotho inhibits pulmonary vascular remodeling by inactivation of Wnt signaling pathway. © 2018 Wiley Periodicals, Inc.

  20. Multimodality optical coherence tomography and fluorescence confocal scanning laser ophthalmoscopy in a zebrafish model of retinal vascular occlusion and remodeling

    Science.gov (United States)

    Li, Xiaoyue; Spitz, Kathleen; Bozic, Ivan; Tao, Yuankai K.

    2018-02-01

    Neovascularization in diabetic retinopathy (DR) and age-related macular degeneration (AMD) result in severe vision-loss and are two of the leading causes of blindness. The structural, metabolic, and vascular changes underlying retinal neovascularization are unknown and, thus, there is an unmet need to identify mechanisms of pathogenesis and novel anti-angiogenic therapies. Zebrafish is a robust ophthalmological model because its retina has comparable structure to the human retina and its fecundity and life-cycle enable development of mutant phenotypes of human pathologies. Here, we perform multimodal imaging with OCT and fluorescence confocal scanning laser ophthalmoscopy (cSLO) to identify changes in retinal structure and function in a zebrafish model of vascular leakage. Transgenic zebrafish with EGFP tagged plasma protein were imaged longitudinally at six time points over two weeks to visualize vascular perfusion changes from diethylaminobenzaldehyde (DEAB) treatment. Complementary contrast from OCT-A perfusion maps and cSLO imaging of plasma protein EGFP shows vascular occlusions posttreatment. cSLO images confirm presence of vessels despite loss of OCT-A signal. Plasma protein EGFP contrast also shows significant changes in vessel structure as compared to baseline images. OCT structural volumes show empty vessel cross-sections confirming non-perfusion. In addition, we present algorithms for automated biometric identification of OCT datasets using OCT-A vascular patterns in the presence of significant vascular perfusion changes. These results establish a framework for large-scale in vivo assays to identify novel anti-angiogenic compounds and understand the mechanisms ofneovascularization associated with retinal ocular pathologies.

  1. Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system

    NARCIS (Netherlands)

    Fiore, Roberto; Rahim, Belquis; Christoffels, Vincent M.; Moorman, Antoon F. M.; Püschel, Andreas W.

    2005-01-01

    The semaphorins are a large family of proteins involved in the patterning of both the vascular and the nervous systems. In order to analyze the function of the membrane-bound semaphorin 5A (Sema5A), we generated mice homozygous for a null mutation in the Sema5a gene. Homozygous null mutants die

  2. JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study.

    Science.gov (United States)

    Milara, Javier; Ballester, Beatriz; Morell, Anselm; Ortiz, José L; Escrivá, Juan; Fernández, Estrella; Perez-Vizcaino, Francisco; Cogolludo, Angel; Pastor, Enrique; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

    2018-06-01

    Pulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation ( V )/perfusion ( Q ) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. The study of JAK2 as potential target to treat PH in IPF. JAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; Ppulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BK Ca ). JAK2 inhibition activated BK Ca channels and reduced intracellular Ca 2+ . JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V / Q mismatching in rats. The animal studies followed the ARRIVE guidelines. JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Excitation-contraction coupling and excitation-transcription coupling in blood vessels: their possible interactions in hypertensive vascular remodeling

    Czech Academy of Sciences Publication Activity Database

    Misárková, Eliška; Behuliak, Michal; Bencze, Michal; Zicha, Josef

    2016-01-01

    Roč. 65, č. 2 (2016), s. 173-191 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NV15-25396A Institutional support: RVO:67985823 Keywords : vascular smooth muscle cells * contractile VSMC phenotype * proliferative VSMC phenotype * cell Ca2+ handling * intracellular signaling pathways Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.461, year: 2016

  4. In vivo evidence for long-term vascular remodeling resulting from chronic cerebral hypoperfusion in mice

    OpenAIRE

    Struys, Tom; Govaerts, Kristof; Oosterlinck, Wouter; Casteels, Cindy; Bronckaers, Annelies; Koole, Michel; Van Laere, Koen; Herijgers, Paul; Lambrichts, Ivo; Himmelreich, Uwe; Dresselaers, Tom

    2016-01-01

    We have characterized both acute and long-term vascular and metabolic effects of unilateral common carotid artery occlusion in mice by in vivo magnetic resonance imaging and positron emission tomography. This common carotid artery occlusion model induces chronic cerebral hypoperfusion and is therefore relevant to both preclinical stroke studies, where it serves as a control condition for a commonly used mouse model of ischemic stroke, and neurodegeneration, as chronic hypoperfusion is causati...

  5. PolNet: A Tool to Quantify Network-Level Cell Polarity and Blood Flow in Vascular Remodeling.

    Science.gov (United States)

    Bernabeu, Miguel O; Jones, Martin L; Nash, Rupert W; Pezzarossa, Anna; Coveney, Peter V; Gerhardt, Holger; Franco, Claudio A

    2018-05-08

    In this article, we present PolNet, an open-source software tool for the study of blood flow and cell-level biological activity during vessel morphogenesis. We provide an image acquisition, segmentation, and analysis protocol to quantify endothelial cell polarity in entire in vivo vascular networks. In combination, we use computational fluid dynamics to characterize the hemodynamics of the vascular networks under study. The tool enables, to our knowledge for the first time, a network-level analysis of polarity and flow for individual endothelial cells. To date, PolNet has proven invaluable for the study of endothelial cell polarization and migration during vascular patterning, as demonstrated by two recent publications. Additionally, the tool can be easily extended to correlate blood flow with other experimental observations at the cellular/molecular level. We release the source code of our tool under the Lesser General Public License. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. Tyrosine phosphorylation of platelet derived growth factor β receptors in coronary artery lesions: implications for vascular remodelling after directional coronary atherectomy and unstable angina pectoris

    Science.gov (United States)

    Abe, J; Deguchi, J; Takuwa, Y; Hara, K; Ikari, Y; Tamura, T; Ohno, M; Kurokawa, K

    1998-01-01

    Background—Growth factors such as platelet derived growth factor (PDGF) have been postulated to be important mediators of neointimal proliferation observed in atherosclerotic plaques and restenotic lesions following coronary interventions. Binding of PDGF to its receptor results in intrinsic receptor tyrosine kinase activation and subsequent cellular migration, proliferation, and vascular contraction.
Aims—To investigate whether the concentration of PDGF β receptor tyrosine phosphorylation obtained from directional coronary atherectomy (DCA) samples correlate with atherosclerotic plaque burden, the ability of diseased vessels to remodel, coronary risk factors, and clinical events.
Methods—DCA samples from 59 patients and 15 non-atherosclerotic left internal thoracic arteries (LITA) were analysed for PDGF β receptor tyrosine phosphorylation content by receptor immunoprecipitation and antiphosphotyrosine western blot. The amount of PDGF β receptor phosphorylation was analysed in relation to angiographic follow up data and clinical variables.
Results—PDGF β receptor tyrosine phosphorylation in the 59 DCA samples was greater than in the 15 non-atherosclerotic LITA (mean (SD) 0.84 (0.67) v 0.17 (0.08) over a control standard, p atherectomy;  restenosis PMID:9616351

  7. Cigarette smoke exposure promotes arterial thrombosis and vessel remodeling after vascular injury in apolipoprotein E-deficient mice.

    Science.gov (United States)

    Schroeter, Marco R; Sawalich, Matthias; Humboldt, Tim; Leifheit, Maren; Meurrens, Kris; Berges, An; Xu, Haiyan; Lebrun, Stefan; Wallerath, Thomas; Konstantinides, Stavros; Schleef, Raymond; Schaefer, Katrin

    2008-01-01

    Cigarette smoking is a major risk factor for the development of cardiovascular disease. However, in terms of the vessel wall, the underlying pathomechanisms of cigarette smoking are incompletely understood, partly due to a lack of adequate in vivo models. Apolipoprotein E-deficient mice were exposed to filtered air (sham) or to cigarette mainstream smoke at a total particulate matter (TPM) concentration of 600 microg/l for 1, 2, 3, or 4 h, for 5 days/week. After exposure for 10 +/- 1 weeks, arterial thrombosis and neointima formation at the carotid artery were induced using 10% ferric chloride. Mice exposed to mainstream smoke exhibited shortened time to thrombotic occlusion (p < 0.01) and lower vascular patency rates (p < 0.001). Morphometric and immunohistochemical analysis of neointimal lesions demonstrated that mainstream smoke exposure increased the amount of alpha-actin-positive smooth muscle cells (p < 0.05) and dose-dependently increased the intima-to-media ratio (p < 0.05). Additional analysis of smooth muscle cells in vitro suggested that 10 microg TPM/ml increased cell proliferation without affecting viability or apoptosis, whereas higher concentrations (100 and 500 microg TPM/ml) appeared to be cytotoxic. Taken together, these findings suggest that cigarette smoking promotes arterial thrombosis and modulates the size and composition of neointimal lesions after arterial injury in apolipoprotein E-deficient mice. Copyright 2008 S. Karger AG, Basel.

  8. Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

    Science.gov (United States)

    Ader, Isabelle; Golzio, Muriel; Andrieu, Guillaume; Zalvidea, Santiago; Richard, Sylvain; Sabbadini, Roger A.; Malavaud, Bernard; Cuvillier, Olivier

    2015-01-01

    Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy. PMID:25915662

  9. Alternatively Activated Macrophages Play an Important Role in Vascular Remodeling and Hemorrhaging in Patients with Brain Arteriovenous Malformation.

    Science.gov (United States)

    Nakamura, Yukihiko; Sugita, Yasuo; Nakashima, Shinji; Okada, Yousuke; Yoshitomi, Munetake; Kimura, Yoshizou; Miyoshi, Hiroaki; Morioka, Motohiro; Ohshima, Koichi

    2016-03-01

    Angiogenic and immunoactive lesions in brain arteriovenous malformation (BAVM) contribute to hemorrhagic events and the growth of BAVMs. However, the detailed mechanism is unclear. Our objective is to clarify the relationship between hemorrhagic events of BAVM and alternatively activated macrophages in the perinidal dilated capillary network (PDCN). We examined microsurgical specimens of BVMs (n = 29) and focused on the PDCN area. Ten autopsied brains without intracranial disease were the controls. We performed immunostaining of the inflammatory and endothelial cell markers, macrophage markers (CD163 and CD68), and vascular endothelial growth factor A (VEGF-A). We evaluated each cell's density and the vessel density in the PDCN and analyzed the relationship to hemorrhagic events of BAVM. The PDCN was involved in all the resected arteriovenous malformations, and these vessels showed a high rate of CD105 expression (72.0 ± 10.64%), indicating newly proliferating vessels. Alternatively activated macrophages were found, with a high rate (85.6%) for all macrophages (controls, 56.6%). In the hemorrhagic cases, the cell density was significantly higher than that in the nonhemorrhagic cases and controls (hemorrhagic group, 290 ± 44 cells/mm(2); nonhemorrhagic group, 180 ± 59 cells/mm(2); and control, 19 ± 8 cells/mm(2)). The cell density of alternatively activated macrophages showed a positive correlation with the vessel density of the PDCN. Double immunostaining showed that VEGF-A was secreted by alternatively activated macrophages. Our data suggest that alternatively activated macrophages may have some relationships with angiogenesis of PDCN and hemorrhagic event of BAVM. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  10. The inflammatory cells in vascular graft anastomosis an electron microscopy study.

    Science.gov (United States)

    Skóra, Jan; Pupka, Artur

    2011-01-01

    In order to determine the processes arising during the healing in vascular grafts the following experiment was desinged in 16 dogs. The animals underwent implantation of unilateral bypass aorto-femoral (straight prosthesis from politetrafluoroethylrne--PTFE). After the 6 months all the animals sacrificed and vascular grafts were dissected and exam in electron microscopy. There were significant differences in the histological findings in structure of neoitima between the proximal and distal anastomoses vascular prostheses. There were evidence of presence of fibroblasts but not macrophages in proximal anastomoses The histological structure of the proximal anastomoses indicates that inflammatory processes was ended during the prosthesis healing. There were presence of macrophages and myofibroblasts, some in the active secretion of collagen in distal anastomoses. Theses images of vascular anastomoses of artery with politerafluoroeth-ylene prosthesis corresponds to the chronic inflammatory reaction in distal anastomoses.

  11. [Association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension].

    Science.gov (United States)

    Wang, Jian-Rong; Zhou, Ying; Sang, Kui; Li, Ming-Xia

    2013-02-01

    To investigate the association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension (HPH). A neonatal rat model of HPH was established as an HPH group, and normal neonatal rats were enrolled as a control group. The mean pulmonary arterial pressure (mPAP) was measured. The percentage of medial thickness to outer diameter of the small pulmonary arteries (MT%) and the percentage of medial cross-section area to total cross-section area of the pulmonary small arteries (MA%) were measured as the indicators for pulmonary vascular remodeling. The immunohistochemical reaction intensities for HIF-1α, ET-1 and iNOS and their mRNA expression in lung tissues of neonatal rats were measured. Correlation analysis was performed to determine the relationship between pulmonary vascular remodeling and mRNA expression of HIF-1α, ET-1 and iNOS. The mPAP of the HPH group kept increasing on days 3, 5, 7, 10, 14, and 21 of hypoxia, with a significant difference compared with the control group (P<0.05). The HPH group had significantly higher MT% and MA% than the control group from day 7 of hypoxia (P<0.05). HIF-1α protein expression increased significantly on days 3, 5, 7 and 10 days of hypoxia, and HIF-1α mRNA expression increased significantly on days 3, 5 and 7 days of hypoxia in the HPH group compared with the control group (P<0.05). ET-1 protein expression increased significantly on days 3, 5 and 7 days of hypoxia and ET-1 mRNA expression increased significantly on day 3 of hypoxia in the HPH group compared with the control group (P<0.05). Both iNOS protein and mRNA expression were significantly higher on days 3, 5 and 7 days of hypoxia than the control group (P<0.05). Both MT% and MA% were positively correlated with HIF-1α mRNA expression (r=0.835 and 0.850 respectively; P<0.05). Pulmonary vascular

  12. Vascular damage after acute local irradiation: a light and electron microscope study

    International Nuclear Information System (INIS)

    Verola, O.; Brocheriou, C.

    1986-01-01

    A pig model was used to examine histological and ultrastructural changes after high-dose local irradiation. This model was chosen to simulate accidents which have occurred in man, enabling the determination of several post-irradiation phases. After an initial phase, with superficial lesions, ischaemic necrosis occurred 3 weeks after irradiation as the result of early vascular alterations. After 2 months, expanding necrosis became obvious in the deep muscle, preceded by an initial spread of vascular lesions: these alterations were obvious from the 30th day by light microscopy but could be detected by electron microscopy from the 9th day. (author)

  13. Global transcriptome analysis reveals extensive gene remodeling, alternative splicing and differential transcription profiles in non-seed vascular plant Selaginella moellendorffii.

    Science.gov (United States)

    Zhu, Yan; Chen, Longxian; Zhang, Chengjun; Hao, Pei; Jing, Xinyun; Li, Xuan

    2017-01-25

    Selaginella moellendorffii, a lycophyte, is a model plant to study the early evolution and development of vascular plants. As the first and only sequenced lycophyte to date, the genome of S. moellendorffii revealed many conserved genes and pathways, as well as specialized genes different from flowering plants. Despite the progress made, little is known about long noncoding RNAs (lncRNA) and the alternative splicing (AS) of coding genes in S. moellendorffii. Its coding gene models have not been fully validated with transcriptome data. Furthermore, it remains important to understand whether the regulatory mechanisms similar to flowering plants are used, and how they operate in a non-seed primitive vascular plant. RNA-sequencing (RNA-seq) was performed for three S. moellendorffii tissues, root, stem, and leaf, by constructing strand-specific RNA-seq libraries from RNA purified using RiboMinus isolation protocol. A total of 176 million reads (44 Gbp) were obtained from three tissue types, and were mapped to S. moellendorffii genome. By comparing with 22,285 existing gene models of S. moellendorffii, we identified 7930 high-confidence novel coding genes (a 35.6% increase), and for the first time reported 4422 lncRNAs in a lycophyte. Further, we refined 2461 (11.0%) of existing gene models, and identified 11,030 AS events (for 5957 coding genes) revealed for the first time for lycophytes. Tissue-specific gene expression with functional implication was analyzed, and 1031, 554, and 269 coding genes, and 174, 39, and 17 lncRNAs were identified in root, stem, and leaf tissues, respectively. The expression of critical genes for vascular development stages, i.e. formation of provascular cells, xylem specification and differentiation, and phloem specification and differentiation, was compared in S. moellendorffii tissues, indicating a less complex regulatory mechanism in lycophytes than in flowering plants. The results were further strengthened by the evolutionary trend of

  14. Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo

    Science.gov (United States)

    The molecular mechanism(s) controlling cell migration during vascular morphogenesis in vivo remain largely undefined. To address this within a physiological context, we used retinaldehyde dehydrogenase-2 (Raldh2) null mouse embryos and demonstrate that retinoic acid (RA) deficiency results in abnorm...

  15. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor.

    Science.gov (United States)

    Howangyin, Kiave-Yune; Zlatanova, Ivana; Pinto, Cristina; Ngkelo, Anta; Cochain, Clément; Rouanet, Marie; Vilar, José; Lemitre, Mathilde; Stockmann, Christian; Fleischmann, Bernd K; Mallat, Ziad; Silvestre, Jean-Sébastien

    2016-03-01

    In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. We generated double-deficient mice for Mertk and Mfge8 (Mertk(-/-)/Mfge8(-/-)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk(-/-)), or Mfge8-deficient (Mfge8(-/-)) animals, Mertk(-/-)/Mfge8(-/-) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C(High and Low) monocytes and macrophages. In parallel, Mertk(-/-)/Mfge8(-/-) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C(High) and Ly6C(How) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C(High)/Ly6C(Low) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre(+)/VEGFA(fl/fl) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart. © 2016 The Authors.

  16. The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded

    Directory of Open Access Journals (Sweden)

    Tyagi Suresh C

    2005-06-01

    Full Text Available Abstract The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans – hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined.

  17. Functional anatomy of the footpad vasculature of dogs: scanning electron microscopy of vascular corrosion casts.

    Science.gov (United States)

    Ninomiya, Hiroyoshi; Akiyama, Emi; Simazaki, Kanae; Oguri, Atsuko; Jitsumoto, Momoko; Fukuyama, Takaaki

    2011-12-01

    Dogs are well adapted to cold climates and they can stand, walk and run on snow and ice for long periods of time. In contrast to the body trunk, which has, dense fur, the paws are more exposed to the cold due to the lack of fur insulation. The extremities have a high surface area-to-volume ratio, so they lose heat very easily. We offer anatomical evidence for a heat-conserving structure associated with dog footpad vasculature. Methylmethacrylate vascular corrosion casts for scanning electron microscopy, Indian ink-injected whole-mount and histological specimens were each prepared, in a series of 16 limbs from four adult dogs. Vascular casts and Indian ink studies showed that abundant venules were arranged around the arteries supplying the pad surface and formed a vein-artery-vein triad, with the peri-arterial venous network intimately related to the arteries. In addition, numerous arteriovenous anastomoses and well-developed venous plexuses were found throughout the dermal vasculature. The triad forms a counter-current heat exchanger. When the footpad is exposed to a cold environment, the counter-current heat exchanger serves to prevent heat loss by recirculating heat back to the body core. Furthermore, the arteriovenous anastomoses shift blood flow, draining blood to the skin surface, and the venous plexuses retain warm blood in the pad surface. Hence, the appropriate temperature for the footpad can be maintained in cold environments. © 2011 The Authors. Veterinary Dermatology. © 2011 ESVD and ACVD.

  18. Electron microscopy study of a vascular prosthesis destructed in vivo reveals fractures in Dacron fibers.

    Science.gov (United States)

    Woźniak, Witold; Olszewski, Wojciech; Górski, Grzegorz

    2016-02-01

    The genuine destruction of a synthetic prosthesis wall, as a late complication of vascular surgery, is extremely rare. We report a case of a 64-year-old male who had his 12-year-old femoropopliteal synthetic graft explanted due to two large pseudoaneurysms in the middle section of the graft. Microscopic evaluation demonstrated the areas of focal thinning along the entire prosthesis wall, with "foreign body" type reaction in the adjacent connective tissue. Transmission electron microscopy showed longitudinal fractures of Dacron fibers interposed with cellular structures, suggesting that destruction must have taken place significantly earlier. The problems of limited graft durability and graft surveillance are discussed. © The Author(s) 2015.

  19. Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function.

    Science.gov (United States)

    Carnevale, Roberto; Sciarretta, Sebastiano; Violi, Francesco; Nocella, Cristina; Loffredo, Lorenzo; Perri, Ludovica; Peruzzi, Mariangela; Marullo, Antonino G M; De Falco, Elena; Chimenti, Isotta; Valenti, Valentina; Biondi-Zoccai, Giuseppe; Frati, Giacomo

    2016-09-01

    The vascular safety of electronic cigarettes (e-Cigarettes) must still be clarified. We compared the impact of e-Cigarettes vs traditional tobacco cigarettes on oxidative stress and endothelial function in healthy smokers and nonsmoker adults. A crossover, single-blind study was performed in 40 healthy subjects (20 smokers and 20 nonsmokers, matched for age and sex). First, all subjects smoked traditional tobacco cigarettes. One week later, the same subjects smoked an e-Cigarette with the same nominal nicotine content. Blood samples were drawn just before and after smoking, and markers of oxidative stress, nitric oxide bioavailability, and vitamin E levels were measured. Flow-mediated dilation (FMD) was also measured. Smoking both e-Cigarettes and traditional cigarettes led to a significant increase in the levels of soluble NOX2-derived peptide and 8-iso-prostaglandin F2α and a significant decrease in nitric oxide bioavailability, vitamin E levels, and FMD. Generalized estimating equation analysis confirmed that all markers of oxidative stress and FMD were significantly affected by smoking and showed that the biologic effects of e-Cigarettes vstraditional cigarettes on vitamin E levels (P = .413) and FMD (P = .311) were not statistically different. However, e-Cigarettes seemed to have a lesser impact than traditional cigarettes on levels of soluble NOX2-derived peptide (P = .001), 8-iso-prostaglandin F2α (P = .046), and nitric oxide bioavailability (P = .001). Our study showed that both cigarettes have unfavorable effects on markers of oxidative stress and FMD after single use, although e-Cigarettes seemed to have a lesser impact. Future studies are warranted to clarify the chronic vascular effects of e-Cigarette smoking. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  20. Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers.

    Science.gov (United States)

    Lemieux, Hélène; Blier, Pierre U; Gnaiger, Erich

    2017-06-06

    Fuel substrate supply and oxidative phosphorylation are key determinants of muscle performance. Numerous studies of mammalian mitochondria are carried out (i) with substrate supply that limits electron flow, and (ii) far below physiological temperature. To analyze potentially implicated biases, we studied mitochondrial respiratory control in permeabilized mouse myocardial fibers using high-resolution respirometry. The capacity of oxidative phosphorylation at 37 °C was nearly two-fold higher when fueled by physiological substrate combinations reconstituting tricarboxylic acid cycle function, compared with electron flow measured separately through NADH to Complex I or succinate to Complex II. The relative contribution of the NADH pathway to physiological respiratory capacity increased with a decrease in temperature from 37 to 25 °C. The apparent excess capacity of cytochrome c oxidase above physiological pathway capacity increased sharply under hypothermia due to limitation by NADH-linked dehydrogenases. This mechanism of mitochondrial respiratory control in the hypothermic mammalian heart is comparable to the pattern in ectotherm species, pointing towards NADH-linked mt-matrix dehydrogenases and the phosphorylation system rather than electron transfer complexes as the primary drivers of thermal sensitivity at low temperature. Delineating the link between stress and remodeling of oxidative phosphorylation is important for understanding metabolic perturbations in disease evolution and cardiac protection.

  1. Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

    Science.gov (United States)

    Silpanisong, Jinjutha; Pearce, William J.

    2015-01-01

    Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia’s remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARγ is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation. PMID:24063376

  2. Bcl-xL-mediated remodeling of rod and cone synaptic mitochondria after postnatal lead exposure: electron microscopy, tomography and oxygen consumption.

    Science.gov (United States)

    Perkins, Guy A; Scott, Ray; Perez, Alex; Ellisman, Mark H; Johnson, Jerry E; Fox, Donald A

    2012-01-01

    Postnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not examined. Thus, our experiments investigated the structural and functional effects of environmentally relevant postnatal lead exposure on rod spherule and cone pedicle mitochondria and whether Bcl-xL overexpression provided neuroprotection. C57BL/6N mice pups were exposed to lead only during lactation via dams drinking water containing lead acetate. The blood [Pb] at weaning was 20.6±4.7 µg/dl, which decreased to the control value by 2 months. To assess synaptic mitochondrial structural differences and vulnerability to lead exposure, wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors were used. Electron microscopy, three-dimensional electron tomography, and retinal and photoreceptor synaptic terminal oxygen consumption (QO(2)) studies were conducted in adult control, Bcl-xL, lead, and Bcl-xL/lead mice. The spherule and pedicle mitochondria in lead-treated mice were swollen, and the cristae structure was markedly changed. In the lead-treated mice, the mitochondrial cristae surface area and volume (abundance: measure correlated with ATP (ATP) synthesis) were decreased in the spherules and increased in the pedicles. Pedicles also had an increased number of crista segments per volume. In the lead-treated mice, the number of segments/crista and fraction of cristae with multiple segments (branching) similarly increased in spherule and pedicle mitochondria. Lead-induced remodeling of spherule mitochondria produced smaller cristae with more branching, whereas pedicle mitochondria had larger cristae with more branching and increased crista junction (CJ) diameter. Lead decreased dark- and light-adapted photoreceptor

  3. Role of Transglutaminase 2 in vascular remodeling

    NARCIS (Netherlands)

    van den Akker, H.H.O.

    2011-01-01

    Verschillende vasculaire ziektebeelden, waaronder hoge bloeddruk en verminderde doorbloeding, leiden tot vernauwing van slagadertjes. Het enzym Transglutaminase 2 (TG2) speelt hierbij een belangrijke rol. Jeroen van den Akker onderzocht het achterliggende proces en ontdekte een nieuwe activatieroute

  4. Scanning electron microscopy of vascular corrosion casts and histologic examination of pulmonary microvasculature in dogs with dirofilariosis.

    Science.gov (United States)

    Ninomiya, Hiroyoshi; Wakao, Yoshito

    2002-11-01

    To characterize structural changes in pulmonary vessels of dogs with dirofilariosis. 8 dogs with dirofilariosis and 2 unaffected control dogs. Pulmonary artery pressure was measured in affected dogs, and dogs then were euthanatized. Scanning electron microscopy was used to examine vascular corrosion casts of pulmonary vasculature. Tissue sections of pulmonary vasculature were evaluated by use of histologic examination. Pulmonary artery pressure was higher in dogs with severely affected pulmonary vessels. In tissue sections, dilatation, as well as lesions in the tunica intima and proliferative lesions resulting in constriction or obstruction, were frequently observed in branches of the pulmonary artery. Numerous dilated bronchial arteries were observed around affected pulmonary arteries. Hyperplastic venous sphincters were observed in small pulmonary veins and venules. In corrosion casts, affected pulmonary lobar arteries had dilatation, pruning, abnormal tapering, constriction, and obstruction. In small arteries and arterioles, surface structures representing aneurisms and edema were seen. Bronchial arteries were well developed and extremely dilated, and they formed numerous anastomoses with pulmonary arteries at all levels, from the pulmonary trunk to peripheral vessels. Capillaries in the lungs were dilated with little structural change. Small pulmonary veins and venules had irregular annular constrictions that were caused by hyperplastic smooth muscle cells of venous sphincters. Scanning electron microscopy of microvascular casts delineated links between the bronchial and pulmonary circulations in dogs with dirofilariosis. Results of scanning electron microscopy provided a structural explanation for the development of pulmonary circulatory disturbances and pulmonary hypertension in dogs affected by dirofilariosis.

  5. Role of arginase in vessel wall remodeling

    Directory of Open Access Journals (Sweden)

    William eDurante

    2013-05-01

    Full Text Available Arginase metabolizes the semi-essential amino acid L-arginine to L-ornithine and urea. There are two distinct isoforms of arginase, arginase I and II, which are encoded by separate genes and display differences in tissue distribution, subcellular localization, and molecular regulation. Blood vessels express both arginase I and II but their distribution appears to be cell-, vessel-, and species-specific. Both isoforms of arginase are induced by numerous pathologic stimuli and contribute to vascular cell dysfunction and vessel wall remodeling in several diseases. Clinical and experimental studies have documented increases in the expression and/or activity of arginase I or II in blood vessels following arterial injury and in pulmonary and arterial hypertension, aging, and atherosclerosis. Significantly, pharmacological inhibition or genetic ablation of arginase in animals ameliorates abnormalities in vascular cells and normalizes blood vessel architecture and function in all of these pathological states. The detrimental effect of arginase in vascular remodeling is attributable to its ability to stimulate vascular smooth muscle cell and endothelial cell proliferation, and collagen deposition by promoting the synthesis of polyamines and L-proline, respectively. In addition, arginase adversely impacts arterial remodeling by directing macrophages towards an inflammatory phenotype. Moreover, the proliferative, fibrotic, and inflammatory actions of arginase in the vasculature are further amplified by its capacity to inhibit nitric oxide synthesis by competing with nitric oxide synthase for substrate, L-arginine. Pharmacologic or molecular approaches targeting specific isoforms of arginase represent a promising strategy in treating obstructive fibroproliferative vascular disease.

  6. Engineering of blood vessel patterns by angio-morphogens [angiotropins]: non-mitogenic copper-ribonucleoprotein cytokins [CuRNP ribokines] with their metalloregulated constituents of RAGE-binding S100-EF-hand proteins and extracellular RNA bioaptamers in vascular remodeling of tissue and angiogenesis in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Wissler, J.H. [ARCONS Applied Research, Bad Nauheim (Germany)

    2001-12-01

    Tissue vascularization is requisite to successful cell-based therapies, biomaterial design and implant integration. Thus, known problems in ossointegration of avascular implants in connection with the generation of bone tissue reflect arrays of general problems of socio-economic relevance existing in reparative medicine still waiting for to be solved. For this purpose, morphogenesis and remodeling of endothelial angio-architectures in tissue and in vitro by isolated non-mitogenic angio-morphogens [angiotropins] are considered in terms of their structure, function and action mechanisms. Extracellular angiotropins are secreted by activated leukocytes/monocytes/macrophages. They are a family of cytokines with morphogen bioactivity selectively directed to endothelial cells. Their structure was deciphered as metalloregulated copper-ribonucleoproteins [CuRNP ribokines]. They are built up of angiotropin-related S100-EF-hand protein [ARP] and highly modified and edited 5'end-phosphorylated RNA [ARNA], complexed together by copper ions. Oxidant-sensitive ARNA and their precursors represent novel types in a RNA world: They are the first isolated and sequenced forms of extracellular RNA [eRNA], may act as cytokine and bioaptamer, contain isoguanosine [crotonoside] as modified nucleoside and show up copper as RNA-structuring transition metal ion. By metalloregulated bioaptamer functions, ARNA impart novel biofunctions to RAGE-binding S100-EF-hand proteins. Angiotropin morphogens were shown suitable for neointiation and remodeling of blood vessel patterns in different, adult, embryonal and artificial tissues. These neovascular patterns manifest regulated hemodynamics for preventing tissue necrosis, supporting tissue functions and promoting wound healing. As evaluated in skin and muscle vascularization, the neovascular patterns are integrated into homeostatic control mechanisms of tissue. Thus, the morphogens show up beneficial perspectives and are suggested useful tools

  7. Callus remodelling model

    Science.gov (United States)

    Miodowska, Justyna; Bielski, Jan; Kromka-Szydek, Magdalena

    2018-01-01

    The objective of this paper is to investigate the healing process of the callus using bone remodelling approach. A new mathematical model of bone remodelling is proposed including both underload and overload resorption, as well as equilibrium and bone growth states. The created model is used to predict the stress-stimulated change in the callus density. The permanent and intermittent loading programs are considered. The analyses indicate that obtaining a sufficiently high values of the callus density (and hence the elasticity) modulus is only possible using time-varying load parameters. The model predictions also show that intermittent loading program causes delayed callus healing. Understanding how mechanical conditions influence callus remodelling process may be relevant in the bone fracture treatment and initial bone loading during rehabilitation.

  8. Acceleration of vascularized bone tissue-engineered constructs in a large animal model combining intrinsic and extrinsic vascularization.

    Science.gov (United States)

    Weigand, Annika; Beier, Justus P; Hess, Andreas; Gerber, Thomas; Arkudas, Andreas; Horch, Raymund E; Boos, Anja M

    2015-05-01

    During the last decades, a range of excellent and promising strategies in Bone Tissue Engineering have been developed. However, the remaining major problem is the lack of vascularization. In this study, extrinsic and intrinsic vascularization strategies were combined for acceleration of vascularization. For optimal biomechanical stability of the defect site and simplifying future transition into clinical application, a primary stable and approved nanostructured bone substitute in clinically relevant size was used. An arteriovenous (AV) loop was microsurgically created in sheep and implanted, together with the bone substitute, in either perforated titanium chambers (intrinsic/extrinsic) for different time intervals of up to 18 weeks or isolated Teflon(®) chambers (intrinsic) for 18 weeks. Over time, magnetic resonance imaging and micro-computed tomography (CT) analyses illustrate the dense vascularization arising from the AV loop. The bone substitute was completely interspersed with newly formed tissue after 12 weeks of intrinsic/extrinsic vascularization and after 18 weeks of intrinsic/extrinsic and intrinsic vascularization. Successful matrix change from an inorganic to an organic scaffold could be demonstrated in vascularized areas with scanning electron microscopy and energy dispersive X-ray spectroscopy. Using the intrinsic vascularization method only, the degradation of the scaffold and osteoclastic activity was significantly lower after 18 weeks, compared with 12 and 18 weeks in the combined intrinsic-extrinsic model. Immunohistochemical staining revealed an increase in bone tissue formation over time, without a difference between intrinsic/extrinsic and intrinsic vascularization after 18 weeks. This study presents the combination of extrinsic and intrinsic vascularization strategies for the generation of an axially vascularized bone substitute in clinically relevant size using a large animal model. The additional extrinsic vascularization promotes tissue

  9. Microvascular Remodeling and Wound Healing: A Role for Pericytes

    Science.gov (United States)

    Dulmovits, Brian M.; Herman, Ira M.

    2012-01-01

    Physiologic wound healing is highly dependent on the coordinated functions of vascular and non-vascular cells. Resolution of tissue injury involves coagulation, inflammation, formation of granulation tissue, remodeling and scarring. Angiogenesis, the growth of microvessels the size of capillaries, is crucial for these processes, delivering blood-borne cells, nutrients and oxygen to actively remodeling areas. Central to angiogenic induction and regulation is microvascular remodeling, which is dependent upon capillary endothelial cell and pericyte interactions. Despite our growing knowledge of pericyte-endothelial cell crosstalk, it is unclear how the interplay among pericytes, inflammatory cells, glia and connective tissue elements shape microvascular injury response. Here, we consider the relationships that pericytes form with the cellular effectors of healing in normal and diabetic environments, including repair following injury and vascular complications of diabetes, such as diabetic macular edema and proliferative diabetic retinopathy. In addition, pericytes and stem cells possessing “pericyte-like” characteristics are gaining considerable attention in experimental and clinical efforts aimed at promoting healing or eradicating ocular vascular proliferative disorders. As the origin, identification and characterization of microvascular pericyte progenitor populations remains somewhat ambiguous, the molecular markers, structural and functional characteristics of pericytes will be briefly reviewed. PMID:22750474

  10. 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.

  11. Chromatin Remodeling and Plant Immunity.

    Science.gov (United States)

    Chen, W; Zhu, Q; Liu, Y; Zhang, Q

    Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance? © 2017 Elsevier Inc. All rights reserved.

  12. NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair.

    Science.gov (United States)

    Wang, Pei; Li, Wen-Lin; Liu, Jian-Min; Miao, Chao-Yu

    2016-06-01

    Vascular repair plays important roles in postischemic remodeling and rehabilitation in cardiovascular and cerebrovascular disease, such as stroke and myocardial infarction. Nicotinamide adenine dinucleotide (NAD), a well-known coenzyme involved in electron transport chain for generation of adenosine triphosphate, has emerged as an important controller regulating various biological signaling pathways. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for NAD biosynthesis in mammals. NAMPT may also act in a nonenzymatic manner, presumably mediated by unknown receptor(s). Rapidly accumulating data in the past decade show that NAMPT and NAMPT-controlled NAD metabolism regulate fundamental biological functions in endothelial cells, vascular smooth muscle cells, and endothelial progenitor cells. The NAD-consuming proteins, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38, may contribute to the regulatory effects of NAMPT-NAD axis in these cells and vascular repair. This review discusses the current data regarding NAMPT and NAMPT-controlled NAD metabolism in vascular repair and the clinical potential translational application of NAMPT-related products in treatment of cardiovascular and cerebrovascular disease.

  13. No-Regrets Remodeling, 2nd Edition

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  14. Pulmonary venous remodeling in COPD-pulmonary hypertension and idiopathic pulmonary arterial hypertension

    DEFF Research Database (Denmark)

    Andersen, Kasper Hasseriis; Andersen, Claus Bøgelund; Gustafsson, Finn

    2017-01-01

    Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive...... pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH......) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic...

  15. Effects of infection with recombinant adenovirus on human vascular endothelial and smooth muscle cells

    NARCIS (Netherlands)

    Quax, P.H.A.; Lamfers, M.L.M.; Grimbergen, J.M.; Teeling, J.; Hoeben, R.C.; Nieuw Amerongen, G.P. van; Hinsbergh, V.W.M. van

    1996-01-01

    The plasminogen activation (PA) system is involved in vascular remodelling. Modulating its activity in vascular cells might be a way to interfere in processes such as angiogenesis and restenosis. Adenoviral vectors have become a favourable tool for direct gene transfer into vascular cells. In the

  16. Role and mechanism of hydrogen sulfide in cigarette smoke induced chronic obstructive pulmonary disease related pulmonary vascular remodeling in rats%硫化氢对吸烟所致慢性阻塞性肺疾病大鼠模型肺血管重塑的作用及机制

    Institute of Scientific and Technical Information of China (English)

    李敏霞; 陈亚红; 廖程程; 林帆; 白宇; 米文君; 孙云; 齐永芬

    2017-01-01

    目的:探讨硫化氢对吸烟所致慢性阻塞性肺疾病(简称慢阻肺)大鼠模型肺血管重塑的作用及机制。方法24只清洁级雄性SD大鼠,按简单随机法分为4组:对照组、吸烟组、吸烟+硫氢化钠( NaHS)组、吸烟+炔丙基甘氨酸( PPG)组。对照组正常喂养,呼吸清洁空气,其余组均采用被动香烟烟雾吸入法构建慢阻肺模型,8周后对相应组的大鼠给予NaHS或PPG药物干预。16周后测定各组肺小动脉血管重塑指标;免疫组织化学方法检测各组肺血管中增殖指标增殖细胞核抗原(PCNA)以及氧化应激指标3-硝基酪氨酸(3-NT)的表达。结果吸烟组气道阻力显著高于对照组(0.859±0.283比0.578±0.088,P<0.05),小气道病理评分明显增高,模型构建成功。吸烟组肺小动脉中膜厚度和完全肌化程度均显著高于对照组、吸烟+NaHS组(0.54±0.20比0.37±0.12、0.39±0.08和0.61±0.16比0.20±0.12、0.34±0.13,均P<0.01),而吸烟+PPG组与吸烟组差异无统计学意义。吸烟组肺血管中PCNA表达均显著高于对照组、吸烟+NaHS组(0.27±0.08比0.12±0.06、0.14±0.06,均P<0.05),吸烟+PPG组与吸烟组差异无统计学意义;与形态学结果相一致。吸烟组3-NT表达显著高于对照组、吸烟+NaHS组(0.26±0.08比0.18±0.04、0.19±0.06,均P<0.01),吸烟+PPG组与吸烟组差异无统计学意义;且肺小动脉中膜厚度与3-NT表达水平呈强相关( r=0.906, P<0.001)。结论硫化氢可显著改善吸烟所致慢阻肺模型的肺血管重塑,可能与其能够减轻氧化应激损伤有关。%Objective To investigate the role and mechanism of hydrogen sulfide ( H2 S ) in rats with chronic obstructive pulmonary disease ( COPD ) related pulmonary vascular remodeling.Methods Twenty four healthy male Sprague-Dawley rats were randomly divided into 4 groups:control group , cigarette smoke (CS

  17. MicroRNAs and vascular remodeling in pulmonary hypertension

    OpenAIRE

    Brock, Matthias

    2012-01-01

    Die pulmonale Hypertonie (PH) ist der Überbegriff für verschiedene Krankheitsbilder, welche in einer signifikanten Erhöhung des Blutdrucks im Lungenkreislauf resultieren und auf Grund des vermehrten rechtsventrikulären Afterloads letztendlich zum Rechtsherzversagen führt. Die chronisch Drucksteigerung in der Lungenblutbahn wird im Wesentlichen durch drei pathogenetische Ereignisse verursacht: eine Mikrothrombosierung der Gefässbahn, eine übermässige Vasokonstriktion, sowie durch einen fibroti...

  18. Mast Cell Inhibition Improves Pulmonary Vascular Remodeling in Pulmonary Hypertension

    NARCIS (Netherlands)

    Bartelds, Beatrijs; van Loon, Rosa Laura E.; Mohaupt, Saffloer; Wijnberg, Hans; Dickinson, Michael G.; Takens, Janny; van Albada, Mirjam; Berger, Rolf M. F.; Boersma, B.

    Background: Pulmonary arterial hypertension (PAH) is a progressive angioproliferative disease with high morbidity and mortality. Although the histopathology is well described, its pathogenesis is largely unknown. We previously identified the increased presence of mast cells and their markers in a

  19. Using Polymeric Scaffolds for Vascular Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Alida Abruzzo

    2014-01-01

    Full Text Available With the high occurrence of cardiovascular disease and increasing numbers of patients requiring vascular access, there is a significant need for small-diameter (<6 mm inner diameter vascular graft that can provide long-term patency. Despite the technological improvements, restenosis and graft thrombosis continue to hamper the success of the implants. Vascular tissue engineering is a new field that has undergone enormous growth over the last decade and has proposed valid solutions for blood vessels repair. The goal of vascular tissue engineering is to produce neovessels and neoorgan tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of tissue-engineered implants is that these tissues can grow, remodel, rebuild, and respond to injury. This review describes the development of polymeric materials over the years and current tissue engineering strategies for the improvement of vascular conduits.

  20. Tribbles 3: A potential player in diabetic aortic remodelling.

    Science.gov (United States)

    Ti, Yun; Xie, Guo-lu; Wang, Zhi-hao; Ding, Wen-yuan; Zhang, Yun; Zhong, Ming; Zhang, Wei

    2016-01-01

    Tribbles 3, whose expression is up-regulated by insulin resistance, was confirmed to be involved in diabetic cardiomyopathy in our previous study. However, it is not known whether Tribbles 3 has a role on conduit arteries such as the aorta in diabetes. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of diabetic rats by serial ultrasonography and histopathologic analyses of aortic wall architecture. Diabetic rats displayed increased aortic medial thickness, excessive collagen deposition, diminished elastic fibres and reduced vascular compliance together with Tribbles 3 overexpression. To further investigate the role of Tribbles 3 in aortic remodelling, we used Tribbles 3 gene silencing in vivo 12 weeks after onset of diabetes. Silence of Tribbles 3 significantly reversed pathological aortic remodelling without blood pressure modification. In Tribbles 3-small interfering RNA group, medial thickness and perivascular fibrosis were markedly decreased; moreover, there were prominent reductions in collagen content and collagen/elastin ratio, resulting in an improved arterial compliance. Additionally, with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased. Silence of Tribbles 3 is potent in mediating reversal of aortic remodelling, implicating that Tribbles 3 is proposed to be a potential therapeutic target for vascular complication in diabetes. © The Author(s) 2015.

  1. Elastin is a key regulator of outward remodeling in arteriovenous fistulas.

    Science.gov (United States)

    Wong, C Y; Rothuizen, T C; de Vries, M R; Rabelink, T J; Hamming, J F; van Zonneveld, A J; Quax, P H A; Rotmans, J I

    2015-04-01

    Maturation failure is the major limitation of arteriovenous fistulas (AVFs) as hemodialysis access conduits. Indeed, 30-50% of AVFs fail to mature due to intimal hyperplasia and insufficient outward remodeling. Elastin has emerged as an important determinant of vascular remodeling. Here the role of elastin in AVF remodeling in elastin haplodeficient (eln(+/-)) mice undergoing AVF surgery has been studied. Unilateral AVFs between the branch of the jugular vein and carotid artery in an end to side manner were created in wild-type (WT) C57BL/6 (n = 11) and in eln(+/-) mice (n = 9). Animals were killed at day 21 and the AVFs were analyzed histologically and at an mRNA level using real-time quantitative polymerase chain reaction. Before AVF surgery, a marked reduction in elastin density in the internal elastic lamina (IEL) of eln(+/-) mice was observed. AVF surgery resulted in fragmentation of the venous internal elastic lamina in both groups while the expression of the tropoelastin mRNA was 53% lower in the eln(+/-) mice than in WT mice (p elastin has an important role in vascular remodeling following AVF creation, in which a lower amount of elastin results in enhanced outward remodeling. Interventions targeting elastin degradation might be a viable option in order to improve AVF maturation. Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  2. Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    Kranenburg, A. R.; de Boer, W. I.; Alagappan, V. K. T.; Sterk, P. J.; Sharma, H. S.

    2005-01-01

    BACKGROUND: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and

  3. Dual roles of heparanase in vascular calcification associated with human carotid atherosclerosis

    DEFF Research Database (Denmark)

    Aldi, S.; Eriksson, L.; Kronqvist, M.

    2017-01-01

    Vascular intimal calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-β-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of heparanase in osteogenesis and bone remodeling...

  4. Impact of bed rest on conduit artery remodeling: effect of exercise countermeasures.

    NARCIS (Netherlands)

    Duijnhoven, N.T.L. van; Green, D.J.; Felsenberg, D.; Belavy, D.L.; Hopman, M.T.E.; Thijssen, D.H.J.

    2010-01-01

    Physical inactivity is a potent stimulus for vascular remodeling, leading to a marked decrease in conduit artery diameter. However, little is known about the impact of physical inactivity on artery wall thickness or wall:lumen ratio or the potential of exercise countermeasures to modify artery wall

  5. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy

    DEFF Research Database (Denmark)

    Ito, H; Koefoed, M; Tiyapatanaputi, P

    2005-01-01

    Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in ...

  6. Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.

    Science.gov (United States)

    Wang, Feng-Wei; Cai, Mu-Yan; Mai, Shi-Juan; Chen, Jie-Wei; Bai, Hai-Yan; Li, Yan; Liao, Yi-Ji; Li, Chang-Peng; Tian, Xiao-Peng; Kung, Hsiang-Fu; Guan, Xin-Yuan; Xie, Dan

    2014-08-30

    Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.

  7. 3D Multiscale Modelling of Angiogenesis and Vascular Tumour Growth

    KAUST Repository

    Perfahl, H.

    2012-11-01

    We present a three-dimensional, multiscale model of vascular tumour growth, which couples nutrient/growth factor transport, blood flow, angiogenesis, vascular remodelling, movement of and interactions between normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. We present computational simulations which show how a vascular network may evolve and interact with tumour and healthy cells. We also demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour.

  8. 3D Multiscale Modelling of Angiogenesis and Vascular Tumour Growth

    KAUST Repository

    Perfahl, H.; Byrne, H. M.; Chen, T.; Estrella, V.; Alarcó n, T.; Lapin, A.; Gatenby, R. A.; Gillies, R. J.; Lloyd, M. C.; Maini, P. K.; Reuss, M.; Owen, M. R.

    2012-01-01

    We present a three-dimensional, multiscale model of vascular tumour growth, which couples nutrient/growth factor transport, blood flow, angiogenesis, vascular remodelling, movement of and interactions between normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. We present computational simulations which show how a vascular network may evolve and interact with tumour and healthy cells. We also demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour.

  9. Remodelling of choroidal blood flow in radiation choroidopathy

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Hideo; Muraoka, Kanemitsu; Takahashi, Kyoichi; Sutoh, Noriko [Gunma Univ., Maebashi (Japan). School of Medicine

    1997-02-01

    Two males, aged 68 and 34 years each, presented with radiation retinopathy. One had received radiation therapy to the whole brain for intracranial metastasis of lung carcinoma 29 months before. The other underwent surgery and radiation for melanoma of the upper eyelid 15 years before. When examined by indocyanine green angiography. both cases showed vasoocclusive changes in the choroid involving the choriocapillaris and major vessels in the affected fundus area. In one eye with severe retinal vascular lesions in the superior temporal quadrant, the vortex vein in the quadrant had obliterated. The venous blood in this quadrant was drained into the inferior temporal vortex vein crossing the presumed watershed zone temporal to the macula. Collaterals had formed between choroidal arteries and between choroidal veins. These cases illustrate that choroidal vascular lesions may be present in radiation retinopathy, that the former may be more pronounced than the latter and that choroidal vessels may undergo extensive remodelling to compensate for the disturbed choroidal circulation. (author)

  10. Remodelling of choroidal blood flow in radiation choroidopathy

    International Nuclear Information System (INIS)

    Kobayashi, Hideo; Muraoka, Kanemitsu; Takahashi, Kyoichi; Sutoh, Noriko

    1997-01-01

    Two males, aged 68 and 34 years each, presented with radiation retinopathy. One had received radiation therapy to the whole brain for intracranial metastasis of lung carcinoma 29 months before. The other underwent surgery and radiation for melanoma of the upper eyelid 15 years before. When examined by indocyanine green angiography. both cases showed vasoocclusive changes in the choroid involving the choriocapillaris and major vessels in the affected fundus area. In one eye with severe retinal vascular lesions in the superior temporal quadrant, the vortex vein in the quadrant had obliterated. The venous blood in this quadrant was drained into the inferior temporal vortex vein crossing the presumed watershed zone temporal to the macula. Collaterals had formed between choroidal arteries and between choroidal veins. These cases illustrate that choroidal vascular lesions may be present in radiation retinopathy, that the former may be more pronounced than the latter and that choroidal vessels may undergo extensive remodelling to compensate for the disturbed choroidal circulation. (author)

  11. 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 ...

  12. 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 ...

  13. Cutaneous remodeling and photorejuvenation using radiofrequency devices

    Directory of Open Access Journals (Sweden)

    Elsaie Mohamed

    2009-01-01

    Full Text Available Radio frequency (RF is electromagnetic radiation in the frequency range of 3-300GHz. The primary effects of RF energy on living tissue are considered to be thermal. The goal of the new devices based on these frequency ranges is to heat specific layers of the skin. The directed use of RF can induce dermal heating and cause collagen degeneration. Wound healing mechanisms promote the remodeling of collagen and wound contraction, which ultimately clinically enhances the appearance of mild to moderate skin laxity. Preliminary studies have reported efficacy in the treatment of laxity that involves the periorbital area and jowls. Because RF energy is not dependent on specific chromophore interaction, epidermal melanin is not at risk of destruction and treatment of all skin types is possible. As such, radiofrequency-based systems have been used successfully for nonablative skin rejuvenation, atrophic scar revision and treatment of unwanted hair, vascular lesions and inflammatory acne. The use of RF is becoming more popular, although a misunderstanding exists regarding the mechanisms and limitations of its actions. This concise review serves as an introduction and guide to many aspects of RF in the non ablative rejuvenation of skin.

  14. Thyroid hormone promotes remodeling of coronary resistance vessels.

    Directory of Open Access Journals (Sweden)

    Olga V Savinova

    Full Text Available Low thyroid hormone (TH function has been linked to impaired coronary blood flow, reduced density of small arterioles, and heart failure. Nonetheless, little is known about the mechanisms by which THs regulate coronary microvascular remodeling. The current study examined the initial cellular events associated with coronary remodeling induced by triiodothyronine (T3 in hypothyroid rats. Rats with established hypothyroidism, eight weeks after surgical thyroidectomy (TX, were treated with T3 for 36 or 72 hours. The early effects of T3 treatment on coronary microvasculature were examined morphometrically. Gene expression changes in the heart were assessed by quantitative PCR Array. Hypothyroidism resulted in arteriolar atrophy in the left ventricle. T3 treatment rapidly induced small arteriolar muscularization and, within 72 hours, restored arteriolar density to control levels. Total length of the capillary network was not affected by TX or T3 treatment. T3 treatment resulted in the coordinate regulation of Angiopoietin 1 and 2 expression. The response of Angiopoietins was consistent with vessel enlargement. In addition to the well known effects of THs on vasoreactivity, these results suggest that THs may affect function of small resistance arteries by phenotypic remodeling of vascular smooth muscle cells (VSMC.

  15. Regulation of bone remodeling by vitamin K2.

    Science.gov (United States)

    Myneni, V D; Mezey, E

    2017-11-01

    All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  16. ECM remodeling and its plasticity

    Science.gov (United States)

    Feng, Jingchen; Jones, Christopher A. R.; Cibula, Matthew; Mao, Xiaoming; Sander, Leonard M.; Levine, Herbert; Sun, Bo

    The mechanical interactions between cells and Extracellular Matrix (ECM) are of great importance in many cellular processes. These interactions are reciprocal, i.e. contracting cells pull and reorganize the surrounding matrix, while the remodeled matrix feeds back to regulate cell activities. Recent experiments show in collagen gels with densely distributed cells, aligned fiber bundles are formed in the direction between neighboring cells. Fibers flow into the center region between contracting cell pairs in this process, which causes the concentration of fibers in the fiber bundles to become significantly enhanced. Using an extended lattice-based model, we show that viscoelasticity plays an essential role in ECM remodeling and contributes to the enhanced concentration in fiber bundles. We further characterize ECM plasticity within our model and verify our results with rheometer experiments.

  17. Chromatin remodeling, development and disease

    International Nuclear Information System (INIS)

    Ko, Myunggon; Sohn, Dong H.; Chung, Heekyoung; Seong, Rho H.

    2008-01-01

    Development is a stepwise process in which multi-potent progenitor cells undergo lineage commitment, differentiation, proliferation and maturation to produce mature cells with restricted developmental potentials. This process is directed by spatiotemporally distinct gene expression programs that allow cells to stringently orchestrate intricate transcriptional activation or silencing events. In eukaryotes, chromatin structure contributes to developmental progression as a blueprint for coordinated gene expression by actively participating in the regulation of gene expression. Changes in higher order chromatin structure or covalent modification of its components are considered to be critical events in dictating lineage-specific gene expression during development. Mammalian cells utilize multi-subunit nuclear complexes to alter chromatin structure. Histone-modifying complex catalyzes covalent modifications of histone tails including acetylation, methylation, phosphorylation and ubiquitination. ATP-dependent chromatin remodeling complex, which disrupts histone-DNA contacts and induces nucleosome mobilization, requires energy from ATP hydrolysis for its catalytic activity. Here, we discuss the diverse functions of ATP-dependent chromatin remodeling complexes during mammalian development. In particular, the roles of these complexes during embryonic and hematopoietic development are reviewed in depth. In addition, pathological conditions such as tumor development that are induced by mutation of several key subunits of the chromatin remodeling complex are discussed, together with possible mechanisms that underlie tumor suppression by the complex

  18. 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.

  19. 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.

  20. Cellular and Molecular Mechanisms of Bone Remodeling*

    OpenAIRE

    Raggatt, Liza J.; Partridge, Nicola C.

    2010-01-01

    Physiological bone remodeling is a highly coordinated process responsible for bone resorption and formation and is necessary to repair damaged bone and to maintain mineral homeostasis. In addition to the traditional bone cells (osteoclasts, osteoblasts, and osteocytes) that are necessary for bone remodeling, several immune cells have also been implicated in bone disease. This minireview discusses physiological bone remodeling, outlining the traditional bone biology dogma in light of emerging ...

  1. Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy.

    Science.gov (United States)

    McCutcheon, Keir; Manga, Pravin

    Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

  2. 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).

  3. Adrenocortical zonation, renewal, and remodeling

    Directory of Open Access Journals (Sweden)

    Marjut ePihlajoki

    2015-03-01

    Full Text Available The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homologue 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation.

  4. 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

  5. Engineering the mechanical and biological properties of nanofibrous vascular grafts for in situ vascular tissue engineering.

    Science.gov (United States)

    Henry, Jeffrey J D; Yu, Jian; Wang, Aijun; Lee, Randall; Fang, Jun; Li, Song

    2017-08-17

    Synthetic small diameter vascular grafts have a high failure rate, and endothelialization is critical for preventing thrombosis and graft occlusion. A promising approach is in situ tissue engineering, whereby an acellular scaffold is implanted and provides stimulatory cues to guide the in situ remodeling into a functional blood vessel. An ideal scaffold should have sufficient binding sites for biomolecule immobilization and a mechanical property similar to native tissue. Here we developed a novel method to blend low molecular weight (LMW) elastic polymer during electrospinning process to increase conjugation sites and to improve the mechanical property of vascular grafts. LMW elastic polymer improved the elasticity of the scaffolds, and significantly increased the amount of heparin conjugated to the micro/nanofibrous scaffolds, which in turn increased the loading capacity of vascular endothelial growth factor (VEGF) and prolonged the release of VEGF. Vascular grafts were implanted into the carotid artery of rats to evaluate the in vivo performance. VEGF treatment significantly enhanced endothelium formation and the overall patency of vascular grafts. Heparin coating also increased cell infiltration into the electrospun grafts, thus increasing the production of collagen and elastin within the graft wall. This work demonstrates that LMW elastic polymer blending is an approach to engineer the mechanical and biological property of micro/nanofibrous vascular grafts for in situ vascular tissue engineering.

  6. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders

    Directory of Open Access Journals (Sweden)

    Sung Sik eChoe

    2016-04-01

    Full Text Available The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue (WAT functions as a key energy reservoir for other organs, whereas the brown adipose tissue (BAT accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secret various hormones, cytokines, and metabolites (termed as adipokines that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic over-nutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.

  7. Chromatin Remodelers: From Function to Dysfunction

    Directory of Open Access Journals (Sweden)

    Gernot Längst

    2015-06-01

    Full Text Available Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development.

  8. Obesity and carotid artery remodeling

    DEFF Research Database (Denmark)

    Kozakova, M; Palombo, C; Morizzo, C

    2015-01-01

    BACKGROUND/OBJECTIVE: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions...... and CCA LD (266 healthy subjects with wide range of body weight (24-159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects...... without CV complications and 88 non-obese subjects matched for gender and age). RESULTS: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile...

  9. Vascularized bone transplant chimerism mediated by vascular endothelial growth factor.

    Science.gov (United States)

    Willems, Wouter F; Larsen, Mikko; Friedrich, Patricia F; Bishop, Allen T

    2015-01-01

    Vascular endothelial growth factor (VEGF) induces angiogenesis and osteogenesis in bone allotransplants. We aim to determine whether bone remodeling in VEGF-treated bone allotransplants results from repopulation with circulation-derived autogenous cells or survival of allogenic transplant-derived cells. Vascularized femoral bone transplants were transplanted from female Dark Agouti rats (DA;RT1(a) ) to male Piebald Viral Glaxo (PVG;RT1(c) ). Arteriovenous bundle implantation and short-term immunosuppression were used to maintain cellular viability. VEGF was encapsulated in biodegradable microspheres and delivered intramedullary in the experimental group (n = 22). In the control group (n = 22), no VEGF was delivered. Rats were sacrificed at 4 or 18 weeks. Laser capture microdissection of bone remodeling areas was performed at the inner and outer cortex. Sex-mismatched genes were quantified with reverse transcription-polymerase chain reaction to determine the amount of male cells to total cells, defined as the relative expression ratio (rER). At 4 weeks, rER was significantly higher at the inner cortex in VEGF-treated transplants as compared to untreated transplants (0.622 ± 0.225 vs. 0.362 ± 0.081, P = 0.043). At 4 weeks, the outer cortex in the control group had a significantly higher rER (P = 0.038), whereas in the VEGF group, the inner cortex had a higher rER (P = 0.015). Over time, in the outer cortex the rER significantly increased to 0.634 ± 0.106 at 18 weeks in VEGF-treated rats (P = 0.049). At 18 weeks, the rER was >0.5 at all cortical areas in both groups. These in vivo findings suggest a chemotactic effect of intramedullary applied VEGF on recipient-derived bone and could imply that more rapid angiogenesis of vascularized allotransplants can be established with microencapsulated VEGF. © 2014 Wiley Periodicals, Inc.

  10. Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

    Science.gov (United States)

    Martinez, Laisel; Duque, Juan C; Tabbara, Marwan; Paez, Angela; Selman, Guillermo; Hernandez, Diana R; Sundberg, Chad A; Tey, Jason Chieh Sheng; Shiu, Yan-Ting; Cheung, Alfred K; Allon, Michael; Velazquez, Omaida C; Salman, Loay H; Vazquez-Padron, Roberto I

    2018-03-01

    The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P =0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P =0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P =0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH. Copyright © 2018 by the American Society of Nephrology.

  11. Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey; Moss, M Elizabeth; Jaffe, Iris Z; Jackson, William F; Dorrance, Anne M

    2017-12-01

    The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia. © 2017 American Heart Association, Inc.

  12. Dynamics of the ethanolamine glycerophospholipid remodeling network.

    Directory of Open Access Journals (Sweden)

    Lu Zhang

    Full Text Available Acyl chain remodeling in lipids is a critical biochemical process that plays a central role in disease. However, remodeling remains poorly understood, despite massive increases in lipidomic data. In this work, we determine the dynamic network of ethanolamine glycerophospholipid (PE remodeling, using data from pulse-chase experiments and a novel bioinformatic network inference approach. The model uses a set of ordinary differential equations based on the assumptions that (1 sn1 and sn2 acyl positions are independently remodeled; (2 remodeling reaction rates are constant over time; and (3 acyl donor concentrations are constant. We use a novel fast and accurate two-step algorithm to automatically infer model parameters and their values. This is the first such method applicable to dynamic phospholipid lipidomic data. Our inference procedure closely fits experimental measurements and shows strong cross-validation across six independent experiments with distinct deuterium-labeled PE precursors, demonstrating the validity of our assumptions. In contrast, fits of randomized data or fits using random model parameters are worse. A key outcome is that we are able to robustly distinguish deacylation and reacylation kinetics of individual acyl chain types at the sn1 and sn2 positions, explaining the established prevalence of saturated and unsaturated chains in the respective positions. The present study thus demonstrates that dynamic acyl chain remodeling processes can be reliably determined from dynamic lipidomic data.

  13. 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

  14. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.

    Science.gov (United States)

    Khalil, Raouf A

    2013-12-15

    Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. 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.

  16. The Latest Twists in Chromatin Remodeling.

    Science.gov (United States)

    Blossey, Ralf; Schiessel, Helmut

    2018-01-05

    In its most restrictive interpretation, the notion of chromatin remodeling refers to the action of chromatin-remodeling enzymes on nucleosomes with the aim of displacing and removing them from the chromatin fiber (the effective polymer formed by a DNA molecule and proteins). This local modification of the fiber structure can have consequences for the initiation and repression of the transcription process, and when the remodeling process spreads along the fiber, it also results in long-range effects essential for fiber condensation. There are three regulatory levels of relevance that can be distinguished for this process: the intrinsic sequence preference of the histone octamer, which rules the positioning of the nucleosome along the DNA, notably in relation to the genetic information coded in DNA; the recognition or selection of nucleosomal substrates by remodeling complexes; and, finally, the motor action on the nucleosome exerted by the chromatin remodeler. Recent work has been able to provide crucial insights at each of these three levels that add new twists to this exciting and unfinished story, which we highlight in this perspective. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  17. Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    A.R. Kranenburg (Andor); W.I. de Boer (Pim); V.K.T. Alagappan (Vijay Kumar Thyagarajan); P.J. Sterk (Peter); H.S. Sharma (Hari)

    2005-01-01

    textabstractBACKGROUND: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in

  18. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

    International Nuclear Information System (INIS)

    Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

    2007-01-01

    The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic

  19. Cell lineage in vascularized bone transplantation.

    Science.gov (United States)

    Willems, Wouter F; Larsen, Mikko; Friedrich, Patricia F; Bishop, Allen T

    2014-01-01

    The biology behind vascularized bone allotransplantation remains largely unknown. We aim to study cell traffic between donor and recipient following bone auto-, and allografting. Vascularized femoral transplantation was performed with arteriovenous bundle implantation and short-term immunosuppression. Twenty male Piebald Virol Glaxo (PVG; RT1(c) ) rats received isotransplants from female PVG (RT1(c) ) rats and 22 male PVG rats received allografts from female Dark Agouti rats (DA, RT1(a) ), representing a major histocompatibility mismatch. Both groups were randomly analyzed at 4 or 18 weeks. Bone remodeling areas (inner and outer cortical samples) were labeled and laser capture microdissected. Analysis of sex-mismatch genes by real-time reverse transcription-polymerase chain reaction provided the relative Expression Ratio (rER) of donor (female) to recipient (male) cells. The rER was 0.456 ± 0.266 at 4 weeks and 0.749 ± 0.387 at 18 weeks (p = 0.09) in allotransplants. In isotransplants, the rER was 0.412 ± 0.239 and 0.467 ± 0.252 at 4 and 18 weeks, respectively (p = 0.21). At 4 weeks, the rER at the outer cortical area of isotransplants was significantly lower in isotransplants as compared with allotransplants (0.247 ± 0.181 vs. 0.549 ± 0.184, p = 0.007). Cells in the inner and outer cortical bone remodeling areas in isotransplants were mainly donor derived (rER 0.5) at 18 weeks. Applying novel methodology, we describe detailed cell traffic in vascularized bone transplants, elaborating our comprehension on bone transplantation. Copyright © 2013 Wiley Periodicals, Inc.

  20. Biomechanical Remodeling of the Diabetic Gastrointestinal Tract

    DEFF Research Database (Denmark)

    Zhao, Jingbo; Liao, Donghua; Yang, Jian

    2010-01-01

    several years, several studies demonstrated that experimental diabetes induces GI morphological and biomechanical remodeling. Following the development of diabetes, the GI wall becomes thicker and the stiffness of the GI wall increases in a time-dependent manner. It is well known that mechanosensitive...... the biomechanical environment of the mechanosensitive nerve endings, therefore, the structure as well as the tension, stress and strain distribution in the GI wall is important for the sensory and motor function. Biomechanical remodeling of diabetic GI tract including alterations of residual strain and increase...

  1. Hypertrophic remodeling of subcutaneous small resistance arteries in patients with Cushing's syndrome.

    Science.gov (United States)

    Rizzoni, Damiano; Porteri, Enzo; De Ciuceis, Carolina; Rodella, Luigi F; Paiardi, Silvia; Rizzardi, Nicola; Platto, Caterina; Boari, Gianluca E M; Pilu, Annamaria; Tiberio, Guido A M; Giulini, Stefano M; Favero, Gaia; Rezzani, Rita; Rosei, Claudia Agabiti; Bulgari, Giuseppe; Avanzi, Daniele; Rosei, Enrico Agabiti

    2009-12-01

    Structural alterations of small resistance arteries in essential hypertensive patients (EH) are mostly characterized by inward eutrophic remodeling. However, we observed hypertrophic remodeling in patients with renovascular hypertension, in those with acromegaly, as well as in patients with non-insulin-dependent diabetes mellitus, suggesting a relevant effect of humoral growth factors on vascular structure, even independent from the hemodynamic load. Cortisol may stimulate the renin-angiotensin system and may induce cardiac hypertrophy. However, presently no data are available about small artery structure in patients with Cushing's syndrome. We have investigated the structure of sc small resistance arteries in 12 normotensive subjects (NT), in 12 EH subjects, and in eight patients with Cushing's syndrome (CS). Small arteries from sc fat were dissected and mounted on a micromyograph. The normalized internal diameter, media thickness, media to lumen ratio, and the media cross-sectional area were measured, as well as indices of oxidative stress. Demographic variables were similar in the three groups, except for clinic blood pressure. The media to lumen ratio was significantly greater in EH and CS, compared with NT; no difference was observed between EH and CS. The media cross-sectional area was significantly greater in CS compared with EH and with NT. An increased vascular oxidative stress was present in CS, as demonstrated by increased levels of superoxide anions, cyclooxygenase-1 and endothelial nitric oxide synthase in the microvessels. Our results suggest the presence of hypertrophic remodeling in sc small resistance arteries of CS, probably as a consequence of growth-promoting properties of circulating cortisol and/or increased vascular oxidative stress.

  2. Markers of Airway Remodeling in Bronchopulmonary Diseases

    Directory of Open Access Journals (Sweden)

    O.Ye. Chernyshova

    2014-10-01

    Full Text Available The article presents information about markers of airway remodeling in bronchopulmonary diseases. There is described the influence of matrix metalloproteinases, tissue inhibitor of matrix metalloproteinase, transforming growth factor, collagen autoantibodies III type, endothelin-1 on the processes of morphological airway reconstruction as smooth muscle hypertrophy, enhanced neovascularization, epithelial cell hyperplasia, collagen deposition, compaction of the basal membrane, observed in bronchial asthma.

  3. Link between vitamin D and airway remodeling

    Directory of Open Access Journals (Sweden)

    Berraies A

    2014-04-01

    Full Text Available Anissa Berraies, Kamel Hamzaoui, Agnes HamzaouiPediatric Respiratory Diseases Department, Abderrahmen Mami Hospital, Ariana, and Research Unit 12SP15 Tunis El Manar University, Tunis, TunisiaAbstract: In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.Keywords: vitamin D, asthma, airway remodeling, airway smooth muscle, supplementation

  4. New predictive model for monitoring bone remodeling

    Czech Academy of Sciences Publication Activity Database

    Bougherara, H.; Klika, Václav; Maršík, František; Mařík, I.; Yahia, L.H.

    95A, č. 1 (2010), s. 9-24 ISSN 1549-3296 R&D Projects: GA ČR GA106/03/1073; GA ČR(CZ) GA106/03/0958 Institutional research plan: CEZ:AV0Z20760514 Keywords : bone remodeling * open system thermodynamics * bone biochemistry Subject RIV: BJ - Thermodynamics Impact factor: 3.044, year: 2010

  5. Relationship of left ventricular, elastic and muscular arteries remodeling in patients with uncontrolled arterial hypertension

    Directory of Open Access Journals (Sweden)

    S. Ya. Dotsenko

    2013-04-01

    ,0%, respectively. Subclinical arterial remodeling was founded in all groups, which was accompanied by an increasing mass of arterial segment and arterial stiffness, but most often in uncontrolled and resistant hypertension. There were unidirectional remodeling of both types of arteries and LV. LV hypertrophy had a direct relationship with the arterial mass by using correlation analysis. Violation of the geometry of both type of arteries was similar to the changes of LV geometry and was more particularly observed in the third group too (more than half of the patients with resistant hypertension had concentric types of remodeling. Thus, concentric hypertrophy of the common carotid artery was found in 42,2% of patients with concentric left ventricular hypertrophy, compared with 3,1% (p <0,05 in the group with normal left ventricular geometry. In contrast, normal left ventricular geometry was associated with normal type of geometry of the common carotid artery in 76.3% of patients, against 11,2% (p <0,05 in the group with concentric left ventricular hypertrophy. Similarly, a close correlation between diastolic dysfunction and arterial stiffness was found. Conclusion. Hence, remodeling of left ventricular, elastic and muscular arteries in uncontrolled and resistant hypertension is systemic and unidirectional. Established relationship between the severity and types of ventricular and arterial remodeling indicates a systemic effect of common pathogenic factors. Overall, these structural changes manifest increasing markers of adverse vascular events, most significantly in uncontrolled and resistant hypertension, which has the negative prognostic significance.

  6. Electronics

    Science.gov (United States)

    2001-01-01

    International Acer Incorporated, Hsin Chu, Taiwan Aerospace Industrial Development Corporation, Taichung, Taiwan American Institute of Taiwan, Taipei, Taiwan...Singapore and Malaysia .5 - 4 - The largest market for semiconductor products is the high technology consumer electronics industry that consumes up...Singapore, and Malaysia . A new semiconductor facility costs around $3 billion to build and takes about two years to become operational

  7. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

    Directory of Open Access Journals (Sweden)

    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  8. Vascular development in the vertebrate pancreas

    Science.gov (United States)

    Azizoglu, D. Berfin; Chong, Diana C.; Villasenor, Alethia; Magenheim, Judith; Barry, David M.; Lee, Simon; Marty-Santos, Leilani; Fu, Stephen; Dor, Yuval; Cleaver, Ondine

    2016-01-01

    The vertebrate pancreas is comprised of a highly branched tubular epithelium, which is intimately associated with an extensive and specialized vasculature. While we know a great deal about basic vascular anatomy of the adult pancreas, as well as islet capillaries, surprisingly little is known about the ontogeny of its blood vessels. Here, we analyze development of the pancreatic vasculature in the mouse embryo. We show that pancreatic epithelial branches intercalate with the fine capillary plexus of the surrounding pancreatic mesenchyme. Endothelial cells (ECs) within this mesenchyme are heterogeneous from the onset of organogenesis. Pancreatic arteries take shape before veins, in a manner analogous to early embryonic vessels. The main central artery forms during mid-gestation, as a result of vessel coalescence and remodeling of a vascular plexus. In addition, we show that vessels in the forming pancreas display a predictable architecture that is dependent on VEGF signaling. Over-expression of VEGF disrupts vascular patterning and arteriovenous differentiation within the developing pancreas. This study constitutes a first-time cellular and molecular characterization of pancreatic blood vessels, as they coordinately grow along with the pancreatic epithelium. PMID:27789228

  9. Vascular development in the vertebrate pancreas.

    Science.gov (United States)

    Azizoglu, D Berfin; Chong, Diana C; Villasenor, Alethia; Magenheim, Judith; Barry, David M; Lee, Simon; Marty-Santos, Leilani; Fu, Stephen; Dor, Yuval; Cleaver, Ondine

    2016-12-01

    The vertebrate pancreas is comprised of a highly branched tubular epithelium, which is intimately associated with an extensive and specialized vasculature. While we know a great deal about basic vascular anatomy of the adult pancreas, as well as islet capillaries, surprisingly little is known about the ontogeny of its blood vessels. Here, we analyze development of the pancreatic vasculature in the mouse embryo. We show that pancreatic epithelial branches intercalate with the fine capillary plexus of the surrounding pancreatic mesenchyme. Endothelial cells (ECs) within this mesenchyme are heterogeneous from the onset of organogenesis. Pancreatic arteries take shape before veins, in a manner analogous to early embryonic vessels. The main central artery forms during mid-gestation, as a result of vessel coalescence and remodeling of a vascular plexus. In addition, we show that vessels in the forming pancreas display a predictable architecture that is dependent on VEGF signaling. Over-expression of VEGF disrupts vascular patterning and arteriovenous differentiation within the developing pancreas. This study constitutes a first-time in-depth cellular and molecular characterization of pancreatic blood vessels, as they coordinately grow along with the pancreatic epithelium. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

    Science.gov (United States)

    Le, Catherine T K; Laidlaw, Grace; Morehouse, Christopher A; Naiman, Brian; Brohawn, Philip; Mustelin, Tomas; Connor, Jane R; McDonald, Donald M

    2015-11-01

    Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Preparation and features of polycaprolactone vascular grafts with the incorporated vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Sevostyanova, V. V., E-mail: sevostyanova.victoria@gmail.com; Khodyrevskaya, Y. I.; Glushkova, T. V.; Antonova, L. V.; Kudryavtseva, Y. A.; Barbarash, O. L.; Barbarash, L. S. [Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo (Russian Federation)

    2015-10-27

    The development of tissue-engineered small-diameter vascular grafts is an urgent issue in cardiovascular surgery. In this study, we assessed how the incorporation of the vascular endothelial growth factor (VEGF) affects morphological and mechanical properties of polycaprolactone (PCL) vascular grafts along with its release kinetics. Vascular grafts were prepared using two-phase electrospinning. In pursuing our aims, we performed scanning electron microscopy, mechanical testing, and enzyme-linked immunosorbent assay. Our results demonstrated the preservation of a highly porous structure and improvement of PCL/VEGF scaffold mechanical properties as compared to PCL grafts. A prolonged VEGF release testifies the use of this construct as a scaffold for tissue-engineered vascular grafts.

  12. Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target?

    Science.gov (United States)

    Agarwal, Puneet; Agarwal, Renu

    2018-06-14

    Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis. Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized. The role of RAS in ECM remodeling is discussed both in terms of its effects on ECM synthesis and its breakdown. The mechanisms of ECM remodeling involving interactions of RAS with transforming growth factor-β, Wnt/β-catenin signaling, bone morphogenic proteins, connective tissue growth factor, and matrix metalloproteinases in ocular tissue are discussed. Expert opinion: Current literature strongly indicates a significant role of RAS in ECM remodeling in TM of hypertensive eyes. Hence, IOP-lowering effect of RAS inhibitors may primarily be attributed to restoration of ECM homeostasis in aqueous outflow pathways rather than its vascular effects. However, the mechanistic targets for RAS inhibitors have much wider distribution and consequences, which remain relatively unexplored in TM.

  13. Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution.

    Directory of Open Access Journals (Sweden)

    Darci M Fink

    Full Text Available The cellular and physiologic mechanisms that regulate the resolution of inflammation remain poorly defined despite their widespread importance in improving inflammatory disease outcomes. We studied the resolution of two cardinal signs of inflammation-pain and swelling-by investigating molecular mechanisms that regulate neural and lymphatic vessel remodeling during the resolution of corneal inflammation. A mouse model of corneal inflammation and wound recovery was developed to study this process in vivo. Administration of nerve growth factor (NGF increased pain sensation and inhibited neural remodeling and lymphatic vessel regression processes during wound recovery. A complementary in vivo approach, the corneal micropocket assay, revealed that NGF-laden pellets stimulated lymphangiogenesis and increased protein levels of VEGF-C. Adult human dermal lymphatic endothelial cells did not express canonical NGF receptors TrkA and p75NTR or activate downstream MAPK- or Akt-pathway effectors in the presence of NGF, although NGF treatment increased their migratory and tubulogenesis capacities in vitro. Blockade of the VEGF-R2/R3 signaling pathway ablated NGF-mediated lymphangiogenesis in vivo. These findings suggest a hierarchical relationship with NGF functioning upstream of the VEGF family members, particularly VEGF-C, to stimulate lymphangiogenesis. Taken together, these studies show that NGF stimulates lymphangiogenesis and that NGF may act as a pathogenic factor that negatively regulates the normal neural and lymphatic vascular remodeling events that accompany wound recovery.

  14. Mechanisms of remodelling of small arteries, antihypertensive therapy and the immune system in hypertension.

    Science.gov (United States)

    Schiffrin, Ernesto L

    2015-12-04

    This review summarizes my lecture for the 2015 Distinguished Scientist Award from the Canadian Society of Clinical Investigation, and is based mainly on studies in my laboratory on the mechanisms of remodelling of small arteries in experimental animal and human hypertension and on treatments that lower blood pressure and improve structure and function of resistance vessels. Small resistance arteries undergo either inward eutrophic or hypertrophic remodelling, which raises blood pressure and impairs tissue perfusion. These vascular changes are corrected by some antihypertensive drugs, which may lead to improved outcomes. Vasoconstriction, growth, oxidative stress and inflammation are some of the mechanisms, within the vascular wall, that can be beneficially affected by antihypertensive agents. These antihypertensive-sensitive mechanisms are reviewed in this review, together with the inflammatory and immune mechanisms that may participate in hypertension and associated cardiovascular injury. Molecular studies, based on this research, will hopefully identify novel diagnostic and therapeutic targets, which will improve our ability to prevent and treat hypertension and cardiovascular disease.

  15. PHAGOCYTOSIS AND REMODELING OF COLLAGEN MATRICES

    OpenAIRE

    Abraham, Leah C.; Dice, J Fred.; Lee, Kyongbum; Kaplan, David L.

    2007-01-01

    The biodegradation of collagen and the deposition of new collagen-based extracellular matrices are of central importance in tissue remodeling and function. Similarly, for collagen-based biomaterials used in tissue engineering, the degradation of collagen scaffolds with accompanying cellular infiltration and generation of new extracellular matrix is critical for integration of in vitro grown tissues in vivo. In earlier studies we observed significant impact of collagen structure on primary lun...

  16. Remodelling of Living Bone - Numerical Simulation

    Czech Academy of Sciences Publication Activity Database

    Klika, V.; Maršík, František; Barsa, P.

    2007-01-01

    Roč. 14, 1+2 (2007), s. 112-117 ISSN 1212-4575. [Lublin-Prague-Sydney Symposium /8./. Lublin, 20.04.2007-21.04.2007] R&D Projects: GA ČR GA106/03/1073; GA MŠk(CZ) 1M06031 Institutional research plan: CEZ:AV0Z20760514 Keywords : bone remodelling * dynamic loading * biochemical model Subject RIV: BO - Biophysics

  17. [Bone remodeling and modeling/mini-modeling.

    Science.gov (United States)

    Hasegawa, Tomoka; Amizuka, Norio

    Modeling, adapting structures to loading by changing bone size and shapes, often takes place in bone of the fetal and developmental stages, while bone remodeling-replacement of old bone into new bone-is predominant in the adult stage. Modeling can be divided into macro-modeling(macroscopic modeling)and mini-modeling(microscopic modeling). In the cellular process of mini-modeling, unlike bone remodeling, bone lining cells, i.e., resting flattened osteoblasts covering bone surfaces will become active form of osteoblasts, and then, deposit new bone onto the old bone without mediating osteoclastic bone resorption. Among the drugs for osteoporotic treatment, eldecalcitol(a vitamin D3 analog)and teriparatide(human PTH[1-34])could show mini-modeling based bone formation. Histologically, mature, active form of osteoblasts are localized on the new bone induced by mini-modeling, however, only a few cell layer of preosteoblasts are formed over the newly-formed bone, and accordingly, few osteoclasts are present in the region of mini-modeling. In this review, histological characteristics of bone remodeling and modeling including mini-modeling will be introduced.

  18. Application of Petri Nets in Bone Remodeling

    Directory of Open Access Journals (Sweden)

    Lingxi Li

    2009-07-01

    Full Text Available Understanding a mechanism of bone remodeling is a challenging task for both life scientists and model builders, since this highly interactive and nonlinear process can seldom be grasped by simple intuition. A set of ordinary differential equations (ODEs have been built for simulating bone formation as well as bone resorption. Although solving ODEs numerically can provide useful predictions for dynamical behaviors in a continuous time frame, an actual bone remodeling process in living tissues is driven by discrete events of molecular and cellular interactions. Thus, an event-driven tool such as Petri nets (PNs, which may dynamically and graphically mimic individual molecular collisions or cellular interactions, seems to augment the existing ODE-based systems analysis. Here, we applied PNs to expand the ODE-based approach and examined discrete, dynamical behaviors of key regulatory molecules and bone cells. PNs have been used in many engineering areas, but their application to biological systems needs to be explored. Our PN model was based on 8 ODEs that described an osteoprotegerin linked molecular pathway consisting of 4 types of bone cells. The models allowed us to conduct both qualitative and quantitative evaluations and evaluate homeostatic equilibrium states. The results support that application of PN models assists understanding of an event-driven bone remodeling mechanism using PN-specific procedures such as places, transitions, and firings.

  19. Novel Mechanism of Plasma Prekallikrein (PK) Activation by Vascular Smooth Muscle Cells: Evidence of the presence of PK Activator

    OpenAIRE

    Keum, Joo-Seob; Jaffa, Miran A; Luttrell, Louis M; Jaffa, Ayad A.

    2014-01-01

    The contribution of plasma prekallikrein (PK) to vascular remodeling is becoming increasingly recognized. Plasma PK is activated when the zymogen PK is digested to an active enzyme by activated factor XII (FXII). Here, we present our findings that vascular smooth muscle cells (VSMC) activate plasma PK in the absence of FXII. Extracted plasma membrane and cytosolic fractions of VSMCs activate PK, but the rate of PK activation was greater by the membrane fraction. FXII neutralizing antibody did...

  20. EMMPRIN-Mediated Induction of Uterine and Vascular Matrix Metalloproteinases during Pregnancy and in Response to Estrogen and Progesterone

    OpenAIRE

    Dang, Yiping; Li, Wei; Tran, Victoria; Khalil, Raouf A.

    2013-01-01

    Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during p...

  1. Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Whitaker, Morgan E; Nair, Vineet; Sinari, Shripad; Dherange, Parinita A; Natarajan, Balaji; Trutter, Lindsey; Brittain, Evan L; Hemnes, Anna R; Austin, Eric D; Patel, Kumar; Black, Stephen M; Garcia, Joe G N; Yuan Md PhD, Jason X; Vanderpool, Rebecca R; Rischard, Franz; Makino, Ayako; Bedrick, Edward J; Desai, Ankit A

    2018-06-01

    Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction. Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension. A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes. Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Assisted reproductive technologies are associated with cardiovascular remodeling in utero that persists postnatally.

    Science.gov (United States)

    Valenzuela-Alcaraz, Brenda; Crispi, Fàtima; Bijnens, Bart; Cruz-Lemini, Monica; Creus, Montserrat; Sitges, Marta; Bartrons, Joaquim; Civico, Salvadora; Balasch, Juan; Gratacós, Eduard

    2013-09-24

    Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1-7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1-6.1]; Pinterquartile range, 1.2-1.5 cm(2)]; atrial area in ART, 1.6 cm(2) [interquartile range, 1.3-1.8 cm(2)]; Pinterquartile range, 67-83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75-94 mm Hg]; Pinterquartile range, 0.45-0.56 mm]; aortic intima-media thickness in ART, 0.64 mm [interquartile range, 0.62-0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility. Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated.

  3. 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....

  4. 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....

  5. Progesterone attenuates airway remodeling and glucocorticoid resistance in a murine model of exposing to ozone.

    Science.gov (United States)

    Zhang, Xue; Bao, Wuping; Fei, Xia; Zhang, Yingying; Zhang, Guoqing; Zhou, Xin; Zhang, Min

    2018-04-01

    Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), a-smooth muscle actin (α-SMA), glycogen synthase kinase-3β (GSK-3β). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1α, VEGF, α-SMA, and GSK-3β in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity. Copyright © 2018. Published by Elsevier Ltd.

  6. Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles

    Directory of Open Access Journals (Sweden)

    Siu-Lung eChan

    2013-06-01

    Full Text Available Angiotensin II is an important determinant of inward remodeling in cerebral arterioles. Many of the vascular effects of angiotensin II are mediated by reactive oxygen species generated from homologues of NADPH oxidase with Nox2 predominating in small arteries and arterioles. Therefore, we tested the hypothesis that superoxide generated by Nox2 plays a role in angiotensin II-induced cerebral arteriolar remodeling. We examined Nox2-deficient and wild-type mice in which a pressor or a non-pressor dose of angiotensin II (1000 or 200 ng/kg/day or saline was infused for 4 weeks via osmotic minipumps. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area (by histology and superoxide level (by hydroethidine staining of cerebral arterioles were determined ex vivo. The pressor, but not the non-pressor, dose of angiotensin II significantly increased systolic arterial pressure in both wild-type and Nox2-deficient mice. Both doses of angiotensin II increased superoxide levels and significantly reduced external diameter in maximally dilated cerebral arterioles in wild-type mice. Increased superoxide and inward remodeling were prevented in Nox2-deficient mice. Moreover, only the pressor dose of AngII increased cross-sectional area of arteriolar wall in wild-type mice and was prevented in Nox2-deficient mice. In conclusion, superoxide derived from Nox2-containing NADPH oxidase plays an important role in angiotensin II-mediated inward remodeling in cerebral arterioles. This effect appears to be independent of pressure and different from that of hypertrophy.

  7. Obesity-induced vascular inflammation involves elevated arginase activity.

    Science.gov (United States)

    Yao, Lin; Bhatta, Anil; Xu, Zhimin; Chen, Jijun; Toque, Haroldo A; Chen, Yongjun; Xu, Yimin; Bagi, Zsolt; Lucas, Rudolf; Huo, Yuqing; Caldwell, Ruth B; Caldwell, R William

    2017-11-01

    Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (ECs) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC-A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high-fat/high-sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular ECs and increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and ECs. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor 2-( S )-amino-6-boronohexanoic acid (ABH). In mouse aortic ECs, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced nitric oxide production and increased A1, TNF-α, VCAM-1, ICAM-1, and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. HFHS diet-induced VAT inflammation is mediated by EC-A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.

  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. 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.

  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. Phenylacetic acid and arterial vascular properties in patients with chronic kidney disease stage 5 on hemodialysis therapy

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Jankowski, Vera; Henning, Lars

    2007-01-01

    Phenylacetic acid (PAA) is a recently described uremic toxin that inhibits inducible nitric oxide synthase expression and plasma membrane calcium ATPase and may therefore also be involved in remodeling of arteries. Such vascular effects have not been evaluated yet in patients with chronic kidney...

  13. Mapping and Quantification of Vascular Branching in Plants, Animals and Humans by VESGEN Software

    Science.gov (United States)

    Parsons-Wingerter, P. A.; Vickerman, M. B.; Keith, P. A.

    2010-01-01

    Humans face daunting challenges in the successful exploration and colonization of space, including adverse alterations in gravity and radiation. The Earth-determined biology of plants, animals and humans is significantly modified in such extraterrestrial environments. One physiological requirement shared by larger plants and animals with humans is a complex, highly branching vascular system that is dynamically responsive to cellular metabolism, immunological protection and specialized cellular/tissue function. VESsel GENeration (VESGEN) Analysis has been developed as a mature beta version, pre-release research software for mapping and quantification of the fractal-based complexity of vascular branching. Alterations in vascular branching pattern can provide informative read-outs of altered vascular regulation. Originally developed for biomedical applications in angiogenesis, VESGEN 2D has provided novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and other microvascular remodeling phenomena. Vascular trees, networks and tree-network composites are mapped and quantified. Applications include disease progression from clinical ophthalmic images of the human retina; experimental regulation of vascular remodeling in the mouse retina; avian and mouse coronary vasculature, and other experimental models in vivo. We envision that altered branching in the leaves of plants studied on ISS such as Arabidopsis thaliana cans also be analyzed.

  14. Experimental Branch Retinal Vein Occlusion Induces Upstream Pericyte Loss and Vascular Destabilization.

    Directory of Open Access Journals (Sweden)

    Elisa Dominguez

    Full Text Available Branch retinal vein occlusion (BRVO leads to extensive vascular remodeling and is important cause of visual impairment. Although the vascular morphological changes following experimental vein occlusion have been described in a variety of models using angiography, the underlying cellular events are ill defined.We here show that laser-induced experimental BRVO in mice leads to a wave of TUNEL-positive endothelial cell (EC apoptosis in the upstream vascular network associated with a transient edema and hemorrhages. Subsequently, we observe an induction of EC proliferation within the dilated vein and capillaries, detected by EdU incorporation, and the edema resolves. However, the pericytes of the upstream capillaries are severely reduced, which was associated with continuing EC apoptosis and proliferation. The vascular remodeling was associated with increased expression of TGFβ, TSP-1, but also FGF2 expression. Exposure of the experimental animals to hypoxia, when pericyte (PC dropout had occurred, led to a dramatic increase in endothelial cell proliferation, confirming the vascular instability induced by the experimental BRVO.Experimental BRVO leads to acute endothelial cells apoptosis and increased permeability. Subsequently the upstream vascular network remains destabilized, characterized by pericyte dropout, un-physiologically high endothelial cells turnover and sensitivity to hypoxia. These early changes might pave the way for capillary loss and subsequent chronic ischemia and edema that characterize the late stage disease.

  15. Role of the Vasa Vasorum and Vascular Resident Stem Cells in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Jun-ichi Kawabe

    2014-01-01

    Full Text Available Atherosclerosis is considered an “inside-out” response, that begins with the dysfunction of intimal endothelial cells and leads to neointimal plaque formation. The adventitia of large blood vessels has been recognized as an active part of the vessel wall that is involved in the process of atherosclerosis. There are characteristic changes in the adventitial vasa vasorum that are associated with the development of atheromatous plaques. However, whether vasa vasorum plays a causative or merely reactive role in the atherosclerotic process is not completely clear. Recent studies report that the vascular wall contains a number of stem/progenitor cells that may contribute to vascular remodeling. Microvessels serve as the vascular niche that maintains the resident stem/progenitor cells of the tissue. Therefore, the vasa vasorum may contribute to vascular remodeling through not only its conventional function as a blood conducting tube, but also its new conceptual function as a stem cell reservoir. This brief review highlights the recent advances contributing to our understanding of the role of the adventitial vasa vasorum in the atherosclerosis and discusses new concept that involves vascular-resident factors, the vasa vasorum and its associated vascular-resident stem cells, in the atherosclerotic process.

  16. PET/CT and vascular disease: Current concepts

    Energy Technology Data Exchange (ETDEWEB)

    Cavalcanti Filho, Jose Leite Gondim; Souza Leao Lima, Ronaldo de [CDPI and Multi-Imagem Clinics, Rio de Janeiro (Brazil); Department of Radiology, Rio de Janeiro Federal University (UFRJ), Rio de Janeiro (Brazil); Souza Machado Neto, Luiz de [CDPI and Multi-Imagem Clinics, Rio de Janeiro (Brazil); Kayat Bittencourt, Leonardo, E-mail: lkayat@terra.com.br [CDPI and Multi-Imagem Clinics, Rio de Janeiro (Brazil); Department of Radiology, Rio de Janeiro Federal University (UFRJ), Rio de Janeiro (Brazil); Cortes Domingues, Romeu [CDPI and Multi-Imagem Clinics, Rio de Janeiro (Brazil); Fonseca, Lea Mirian Barbosa da [CDPI and Multi-Imagem Clinics, Rio de Janeiro (Brazil); Department of Radiology, Rio de Janeiro Federal University (UFRJ), Rio de Janeiro (Brazil)

    2011-10-15

    Since its introduction in 2001, positron emission tomography associated to computed tomography (PET/CT) has been established as a standard tool in cancer evaluation. Being a multimodality imaging method, it combines in a single session the sensitivity granted by PET for detection of molecular targets within the picomolar range, with an underlying submilimetric resolution inherent to CT, that can precisely localize the PET findings. In this last decade, there have been new insights regarding the pathophysiology of atherosclerosis, particularly about plaque rupture and vascular remodeling. This has increased the interest for research on PET/CT in vascular diseases as a potential new diagnostic tool, since some PET molecular targets could identify diseases before the manifestation of gross anatomic features. In this review, we will describe the current applications of PET/CT in vascular diseases, emphasizing its usefulness in the settings of vasculitis, aneurysms, vascular graft infection, aortic dissection, and atherosclerosis/plaque vulnerability. Although not being properly peripheral vascular conditions, ischemic cardiovascular disease and cerebrovascular disease will be briefly addressed as well, due to their widespread prevalence and importance.

  17. GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.

    Science.gov (United States)

    Liu, Liu; Kashyap, Shreya; Murphy, Brennah; Hutson, Dillion D; Budish, Rebecca A; Trimmer, Emma H; Zimmerman, Margaret A; Trask, Aaron J; Miller, Kristin S; Chappell, Mark C; Lindsey, Sarah H

    2016-04-15

    The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;PTreatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage. Copyright © 2016 the American Physiological Society.

  18. 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

  19. 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)

  20. Constructive remodeling of biologic scaffolds is dependent on early exposure to physiologic bladder filling in a canine partial cystectomy model.

    Science.gov (United States)

    Boruch, Alan V; Nieponice, Alejandro; Qureshi, Irfan R; Gilbert, Thomas W; Badylak, Stephen F

    2010-06-15

    Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate the constructive remodeling of several tissue types. Previous studies suggest that the ECM scaffold remodeling process is dependent on microenvironmental factors, including tissue-specific biomechanical loading. The objective of the present study was to evaluate the effects of long-term catheterization (LTC), with its associated inhibition of bladder filling and physiologic biomechanical loading, on ECM scaffold remodeling following partial cystectomy in a canine model. Reconstruction of the partial cystectomy site was performed using ECM scaffolds prepared from porcine small intestinal submucosa (SIS) or porcine urinary bladder matrix (UBM). Animals were randomly assigned to either a long-term catheterization (LTC) group (n=5, catheterized 28 d) or a short-term catheterization group (STC, n=5, catheterized 24 h), and scaffold remodeling was assessed by histologic methods at 4 and 12 wk postoperatively. By 4 wk, animals in the STC group showed a well-developed and highly differentiated urothelium, a robust vascularization network, abundant smooth muscle actin (SMA), and smooth muscle myosin heavy chain (smMHC) expressing spindle-shaped cells, and many neuronal processes associated with newly formed arterioles. In contrast, at 4 wk the scaffolds in LTC animals were not epithelialized, and did not express neuronal markers. The scaffolds in the LTC group developed a dense granulation tissue containing SMA+, smMHC-, spindle-shaped cells that were morphologically and phenotypically consistent with myofibroblasts, but not smooth muscle cells. By 12 wk postoperatively, the ECM scaffolds in the STC animals showed a constructive remodeling response, with a differentiated urothelium and islands of smooth muscle cells within the remodeled scaffold. In contrast, at 12 wk the scaffolds in LTC animals had a remodeling response more consistent with fibrosis even though catheters had been

  1. CHD chromatin remodelers and the transcription cycle

    Science.gov (United States)

    Murawska, Magdalena

    2011-01-01

    It is well established that ATP-dependent chromatin remodelers modulate DNA access of transcription factors and RNA polymerases by “opening” or “closing” chromatin structure. However, this view is far too simplistic. Recent findings have demonstrated that these enzymes not only set the stage for the transcription machinery to act but also are actively involved at every step of the transcription process. As a consequence, they affect initiation, elongation, termination and RNA processing. In this review we will use the CHD family as a paradigm to illustrate the progress that has been made in revealing these new concepts. PMID:22223048

  2. Transcriptional networks and chromatin remodeling controlling adipogenesis

    DEFF Research Database (Denmark)

    Siersbæk, Rasmus; Nielsen, Ronni; Mandrup, Susanne

    2012-01-01

    Adipocyte differentiation is tightly controlled by a transcriptional cascade, which directs the extensive reprogramming of gene expression required to convert fibroblast-like precursor cells into mature lipid-laden adipocytes. Recent global analyses of transcription factor binding and chromatin...... remodeling have revealed 'snapshots' of this cascade and the chromatin landscape at specific time-points of differentiation. These studies demonstrate that multiple adipogenic transcription factors co-occupy hotspots characterized by an open chromatin structure and specific epigenetic modifications....... Such transcription factor hotspots are likely to represent key signaling nodes which integrate multiple adipogenic signals at specific chromatin sites, thereby facilitating coordinated action on gene expression....

  3. Chromatin remodelling: the industrial revolution of DNA around histones.

    Science.gov (United States)

    Saha, Anjanabha; Wittmeyer, Jacqueline; Cairns, Bradley R

    2006-06-01

    Chromatin remodellers are specialized multi-protein machines that enable access to nucleosomal DNA by altering the structure, composition and positioning of nucleosomes. All remodellers have a catalytic ATPase subunit that is similar to known DNA-translocating motor proteins, suggesting DNA translocation as a unifying aspect of their mechanism. Here, we explore the diversity and specialization of chromatin remodellers, discuss how nucleosome modifications regulate remodeller activity and consider a model for the exposure of nucleosomal DNA that involves the use of directional DNA translocation to pump 'DNA waves' around the nucleosome.

  4. Centriole Remodeling during Spermiogenesis in Drosophila.

    Science.gov (United States)

    Khire, Atul; Jo, Kyoung H; Kong, Dong; Akhshi, Tara; Blachon, Stephanie; Cekic, Anthony R; Hynek, Sarah; Ha, Andrew; Loncarek, Jadranka; Mennella, Vito; Avidor-Reiss, Tomer

    2016-12-05

    The first cell of an animal (zygote) requires centrosomes that are assembled from paternally inherited centrioles and maternally inherited pericentriolar material (PCM) [1]. In some animals, sperm centrioles with typical ultrastructure are the origin of the first centrosomes in the zygote [2-4]. In other animals, however, sperm centrioles lose their proteins and are thought to be degenerated and non-functional during spermiogenesis [5, 6]. Here, we show that the two sperm centrioles (the giant centriole [GC] and the proximal centriole-like structure [PCL]) in Drosophila melanogaster are remodeled during spermiogenesis through protein enrichment and ultrastructure modification in parallel to previously described centrosomal reduction [7]. We found that the ultrastructure of the matured sperm (spermatozoa) centrioles is modified dramatically and that the PCL does not resemble a typical centriole. We also describe a new phenomenon of Poc1 enrichment of the atypical centrioles in the spermatozoa. Using various mutants, protein expression during spermiogenesis, and RNAi knockdown of paternal Poc1, we found that paternal Poc1 enrichment is essential for the formation of centrioles during spermiogenesis and for the formation of centrosomes after fertilization in the zygote. Altogether, these findings demonstrate that the sperm centrioles are remodeled both in their protein composition and in ultrastructure, yet they are functional and are essential for normal embryogenesis in Drosophila. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. MicroRNAs in right ventricular remodelling.

    Science.gov (United States)

    Batkai, Sandor; Bär, Christian; Thum, Thomas

    2017-10-01

    Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

  6. 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.

  7. Reactive oxygen species, cell growth, cell cycle progression and vascular remodeling in hypertension

    Czech Academy of Sciences Publication Activity Database

    Vokurková, Martina; Xu, S.; Touyz, R.M.

    2007-01-01

    Roč. 3, č. 1 (2007), s. 53-63 ISSN 1479-6678 R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : cyclins * oxidative stress * cell proliferation Subject RIV: ED - Physiology

  8. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

    Science.gov (United States)

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene

    2014-01-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice. PMID:25539853

  9. Exercise facilitates early recognition of cardiac and vascular remodeling in chronic thromboembolic pulmonary hypertension in swine.

    Science.gov (United States)

    Stam, Kelly; van Duin, Richard W B; Uitterdijk, André; Cai, Zongye; Duncker, Dirk J; Merkus, Daphne

    2018-03-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of patients after pulmonary embolism and is accompanied by an impaired exercise tolerance, which is ascribed to the increased right ventricular (RV) afterload in combination with a ventilation/perfusion (V/Q) mismatch in the lungs. The present study aimed to investigate changes in arterial Po 2 and hemodynamics in response to graded treadmill exercise during development and progression of CTEPH in a novel swine model. Swine were chronically instrumented and received multiple pulmonary embolisms by 1) microsphere infusion (Spheres) over 5 wk, 2) endothelial dysfunction by administration of the endothelial nitric oxide synthase inhibitor N ω -nitro-l-arginine methyl ester (L-NAME) for 7 wk, 3) combined pulmonary embolisms and endothelial dysfunction (L-NAME + Spheres), or 4) served as sham-operated controls (sham). After a 9 wk followup, embolization combined with endothelial dysfunction resulted in CTEPH, as evidenced by mean pulmonary artery pressures of 39.5 ± 5.1 vs. 19.1 ± 1.5 mmHg (Spheres, P swine to result in an exercise-induced increase in cardiac index. In conclusion, embolization in combination with endothelial dysfunction results in CTEPH in swine. Exercise increased RV afterload, exacerbated the V/Q mismatch, and unmasked RV dysfunction. NEW & NOTEWORTHY Here, we present the first double-hit chronic thromboembolic pulmonary hypertension swine model. We show that embolization as well as endothelial dysfunction is required to induce sustained pulmonary hypertension, which is accompanied by altered exercise hemodynamics and an exacerbated ventilation/perfusion mismatch during exercise.

  10. Epigenetic histone acetylation modifiers in vascular remodelling : New targets for therapy in cardiovascular disease

    NARCIS (Netherlands)

    Pons, D.; Vries, F.R. de; Elsen, P.J. van den; Heijmans, B.T.; Quax, P.H.A.; Jukema, J.W.

    2009-01-01

    Significant progress has been made in the clinical management of a variety of cardiovascular diseases. Nevertheless, the therapeutic efficacy of the current treatment modalities for atherosclerosis and restenosis is not fully sufficient in a large proportion of patients. One of the major

  11. Galectin-3 and post-myocardial infarction cardiac remodeling

    NARCIS (Netherlands)

    Meijers, Wouter C.; van der Velde, A. Rogier; Pascual-Figal, Domingo A.; de Boer, Rudolf A.

    2015-01-01

    This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling. Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in

  12. Negative remodeling at the ostium of the left circumflex artery.

    Science.gov (United States)

    Kobayashi, Y; Mehran, R; Moussa, I; Reyes, A; Moses, J W

    2001-12-01

    We report an ostial lesion with negative remodeling. Coronary angiography revealed a 60% stenosis at the ostium of the left circumflex artery (LCX). Intravascular ultrasound (IVUS)-guided directional atherectomy followed by stenting was planned. However, IVUS images revealed no significant stenosis and negative remodeling at the ostium of the LCX. The lesion did not undergo intervention.

  13. The behavior of adaptive bone-remodeling simulation models

    NARCIS (Netherlands)

    H.H. Weinans (Harrie); R. Huiskes (Rik); H.J. Grootenboer

    1992-01-01

    textabstractThe process of adaptive bone remodeling can be described mathematically and simulated in a computer model, integrated with the finite element method. In the model discussed here, cortical and trabecular bone are described as continuous materials with variable density. The remodeling rule

  14. Selected biological markers in various vascular lesions of the head and neck

    Directory of Open Access Journals (Sweden)

    Zuzanna Gronkiewicz

    2014-10-01

    Full Text Available Vascular anomalies are divided according to the contemporary system of classification into two groups: tumors and malformations. However, there is no consensus on juvenile angiofibroma’s place in that system. The general characteristics of selected markers of angiogenesis and tissue remodeling are presented in the series in the context of current knowledge in the field of pathophysiology of vascular lesions. The mentioned markers are currently the subjects of multidirectional studies in oncology, as they take part in the process of neoangiogenesis and proliferation of tumors. Nevertheless, they have not been widely examined in vascular lesions. The indirect goal of that series is to indicate the possible research direction on vascular lesions to determine their molecular profile, to create a more specific system of classification, and above all to develop new diagnostic and treatment methods.

  15. Pulmonary vascular complications in portal hypertension and liver disease: A concise review

    Directory of Open Access Journals (Sweden)

    M. Porres-Aguilar

    2013-01-01

    Full Text Available Chronic liver disease and/or portal hypertension may be associated with one of the two pulmonary vascular complications: portopulmonary hypertension and hepatopulmonary syndrome. These pulmonary vascular disorders are notoriously underdiagnosed; however, they have a substantial negative impact on survival and require special attention in order to understand their diagnostic approach and to select the best therapeutic options. Portopulmonary hypertension results from excessive vasoconstriction, vascular remodeling, and proliferative and thrombotic events within the pulmonary circulation that lead to progressive right ventricular failure and ultimately to death. On the other hand, abnormal intrapulmonary vascular dilations, profound hypoxemia, and a wide alveolar-arterial gradient are the hallmarks of the hepatopulmonary syndrome, resulting in difficult-to-treat hypoxemia. The aim of this review is to summarize the latest pathophysiologic concepts, diagnostic approach, therapy, and prognosis of portopulmonary hypertension and hepatopulmonary syndrome, as well as to discuss the role of liver transplantation as a definitive therapy in selected patients with these conditions.

  16. 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.)

  17. Molecular mechanisms of synaptic remodeling in alcoholism.

    Science.gov (United States)

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism. Published by Elsevier Ireland Ltd.

  18. Matrix Remodeling in Pulmonary Fibrosis and Emphysema

    Science.gov (United States)

    O’Reilly, Philip; Antony, Veena B.; Gaggar, Amit

    2016-01-01

    Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema. PMID:26741177

  19. Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits

    Science.gov (United States)

    Sebel, Luke E; Graves, Steven M; Chan, C Savio; Surmeier, D James

    2017-01-01

    Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics. PMID:27577602

  20. Experimental absorbable stent permits airway remodeling.

    Science.gov (United States)

    Liu, Kuo-Sheng; Liu, Yun-Hen; Peng, Yi-Jie; Liu, Shih-Jung

    2011-02-01

    Despite metallic and silicone stents being effective in treating various airway lesions, many concerns still remain. A bioresorbable stent that scaffolds the airway lumen and dissolves after the remodeling process is completed has advantages over metallic and silicone stents. We designed and fabricated a new mesh-type bioresorbable stent with a backbone of polycaprolactone (PCL), and evaluated its safety and biocompatibility in a rabbit trachea model. The PCL stent was fabricated by a laboratory-made microinjection molding machine. In vitro mechanical strength of the PCL stents was tested and compared to that of commercial silicone stents. The bioresorbable stents were surgically implanted into the cervical trachea of New Zealand white rabbits (n=6). Animals received bronchoscopic examination at 1, 2, 4, 8, and 12 weeks after surgery. Histological examination was completed to evaluate the biocompatibility of the stents. No animals died during the period of study. Distal stent migration was noted in 1 rabbit. In-stent secretion accumulation was found in 2 rabbits. Histological examination showed intact ciliated epithelium and marked leukocyte infiltration in the submucosa of the stented area at 10 and 28 weeks. Stent degradation was minimal, and the mechanical strength was well preserved at the end of 33 weeks. These preliminary findings showed good safety and biocompatibility of the new PCL stent when used in the airway remodeling. PCL could be a promising bioresorbable material for stent design if prolonged degradation time is required. Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  1. Vitamin D in Vascular Calcification: A Double-Edged Sword?

    Directory of Open Access Journals (Sweden)

    Jeffrey Wang

    2018-05-01

    Full Text Available Vascular calcification (VC as a manifestation of perturbed mineral balance, is associated with aging, diabetes and kidney dysfunction, as well as poorer patient outcomes. Due to the current limited understanding of the pathophysiology of vascular calcification, the development of effective preventative and therapeutic strategies remains a significant clinical challenge. Recent evidence suggests that traditional risk factors for cardiovascular disease, such as left ventricular hypertrophy and dyslipidaemia, fail to account for clinical observations of vascular calcification. Therefore, more complex underlying processes involving physiochemical changes to mineral balance, vascular remodelling and perturbed hormonal responses such as parathyroid hormone (PTH and fibroblast growth factor 23 (FGF-23 are likely to contribute to VC. In particular, VC resulting from modifications to calcium, phosphate and vitamin D homeostasis has been recently elucidated. Notably, deregulation of vitamin D metabolism, dietary calcium intake and renal mineral handling are associated with imbalances in systemic calcium and phosphate levels and endothelial cell dysfunction, which can modulate both bone and soft tissue calcification. This review addresses the current understanding of VC pathophysiology, with a focus on the pathogenic role of vitamin D that has provided new insights into the mechanisms of VC.

  2. The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

    Science.gov (United States)

    Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

    2014-01-01

    Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID

  3. Differential expression of proteoglycans in tissue remodeling and lymphangiogenesis after experimental renal transplantation in rats.

    Directory of Open Access Journals (Sweden)

    Heleen Rienstra

    Full Text Available BACKGROUND: Chronic transplant dysfunction explains the majority of late renal allograft loss and is accompanied by extensive tissue remodeling leading to transplant vasculopathy, glomerulosclerosis and interstitial fibrosis. Matrix proteoglycans mediate cell-cell and cell-matrix interactions and play key roles in tissue remodeling. The aim of this study was to characterize differential heparan sulfate proteoglycan and chondroitin sulfate proteoglycan expression in transplant vasculopathy, glomerulosclerosis and interstitial fibrosis in renal allografts with chronic transplant dysfunction. METHODS: Renal allografts were transplanted in the Dark Agouti-to-Wistar Furth rat strain combination. Dark Agouti-to-Dark Agouti isografts and non-transplanted Dark Agouti kidneys served as controls. Allograft and isograft recipients were sacrificed 66 and 81 days (mean after transplantation, respectively. Heparan sulfate proteoglycan (collXVIII, perlecan and agrin and chondroitin sulfate proteoglycan (versican expression, as well as CD31 and LYVE-1 (vascular and lymphatic endothelium, respectively expression were (semi- quantitatively analyzed using immunofluorescence. FINDINGS: Arteries with transplant vasculopathy and sclerotic glomeruli in allografts displayed pronounced neo-expression of collXVIII and perlecan. In contrast, in interstitial fibrosis expression of the chondroitin sulfate proteoglycan versican dominated. In the cortical tubular basement membranes in both iso- and allografts, induction of collXVIII was detected. Allografts presented extensive lymphangiogenesis (p<0.01 compared to isografts and non-transplanted controls, which was associated with induced perlecan expression underneath the lymphatic endothelium (p<0.05 and p<0.01 compared to isografts and non-transplanted controls, respectively. Both the magnitude of lymphangiogenesis and perlecan expression correlated with severity of interstitial fibrosis and impaired graft function

  4. Vascular cognitive impairments in chronic kidney disease

    Directory of Open Access Journals (Sweden)

    I. V. Rogova

    2015-01-01

    Full Text Available Objective: to study the specific features of development of cognitive impairments (CIs, the role of traditional cardiovascular risk factors and renal failure-induced factors in patients with Stages I–IV chronic kidney disease (CKD and to assess an association of CIs with the signs of vascular wall remodeling in them. Patients and methods. Fifty-one patients aged 53±10 years with CKD were examined. Among them, there were 20 patients with Stages I–II CKD: a glomerular filtration rate (GFR of і60 ml/min/1.73 m2, signs of renal lesion; 20 with Stages III CKD: a GFR of <60–30 ml/min/1.73 m2, and 11 with Stages VI CKD: a GFR of <30–15 ml/min/1.73 m2. Results and discussion. CIs were more common in the patients with Stages III–IV than in those with Stages I–II, as shown by the scores of the mini-mental state examination (p<0.001, the frontal assessment battery (p=0.001, and the regulatory function test (p<0.001. These tests showed that the magnitude of CIs increased with the higher stage of CKD. Stages III–IV CKD is an independent predictor of CIs in persons with predialysis-stage kidney lesion. CIs were found to be related to hyperhomocysteinemia, anemia, abdominal obesity, left ventricular hypertrophy, and patient age. The signs of atherosclerotic lesion of the common carotid arteries and the indicators of arterial stiffness were also associated with the incidence and magnitude of CIs in CKD. The detection of CIs in patients with early CKD allows one to timely initiate adequate therapy aimed particularly at improving cerebral circulation, eliminating the impact of risk factors, and slowing down the vascular remodeling. The management tactics for patients with CKD must involve the identification and correction of cardiovascular risk factors, and duplex scanning of the wall of the common carotid arteries may be used as a noninvasive method to assess the risk of the development and progression of CIs in predialysis CKD. 

  5. Atorvastatin Protects Vascular Smooth Muscle Cells From TGF-β1-Stimulated Calcification by Inducing Autophagy via Suppression of the β-Catenin Pathway

    Directory of Open Access Journals (Sweden)

    Demin Liu

    2014-01-01

    Full Text Available Background: Arterial calcification is a major event in the progression of atherosclerosis. It is reported that statins exhibit various protective effects against vascular smooth muscle cell (VSMC inflammation and proliferation in cardiovascular remodeling. Although statins counteract atherosclerosis, the molecular mechanisms of statins on the calcium release from VSMCs have not been clearly elucidated. Methods: Calcium content of VSMCs was measured using enzyme-linked immunosorbent assay (ELISA. The expression of proteins involved in cellular transdifferentiation was analyzed by western blot. Cell autophagy was measured by fluorescence microscopic analysis for acridine orange staining and transmission electron microscopy analysis. The autophagic inhibitors (3-MA, chloroquine, NH4Cl and bafilomycin A1 and β-catenin inhibitor JW74 were used to assess the effects of atorvastatin on autophagy and the involvement of β-catenin on cell calcification respectively. Furthermore, cell transfection was performed to overexpress β-catenin. Results: In VSMCs, atorvastatin significantly suppressed transforming growth factor-β1 (TGF-β1-stimulated calcification, accompanied by the induction of autophagy. Downregulation of autophagy with autophagic inhibitors significantly suppressed the inhibitory effect of atorvastatin on cell calcification. Moreover, the beneficial effect of atorvastatin on calcification and autophagy was reversed by β-catenin overexpression. Conversely, JW74 supplement enhanced this effect. Conclusion: These data demonstrated that atorvastatin protect VSMC from TGF-β1-stimulated calcification by inducing autophagy through suppression of the β-catenin pathway, identifying autophagy induction might be a therapeutic strategy for use in vascular calcification.

  6. 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

  7. Phosphorus starvation induces membrane remodeling and recycling in Emiliania huxleyi.

    Science.gov (United States)

    Shemi, Adva; Schatz, Daniella; Fredricks, Helen F; Van Mooy, Benjamin A S; Porat, Ziv; Vardi, Assaf

    2016-08-01

    Nutrient availability is an important factor controlling phytoplankton productivity. Phytoplankton contribute c. 50% of the global photosynthesis and possess efficient acclimation mechanisms to cope with nutrient stress. We investigate the cellular response of the bloom-forming coccolithophore Emiliania huxleyi to phosphorus (P) scarcity, which is often a limiting factor in marine ecosystems. We combined mass spectrometry, fluorescence microscopy, transmission electron microscopy (TEM) and gene expression analyses in order to assess diverse cellular features in cells exposed to P limitation and recovery. Early starvation-induced substitution of phospholipids in the cells' membranes with galacto- and betaine lipids. Lipid remodeling was rapid and reversible upon P resupply. The PI3K inhibitor wortmannin reduced phospholipid substitution, suggesting a possible involvement of PI3K- signaling in this process. In addition, P limitation enhanced the formation and acidification of membrane vesicles in the cytoplasm. Intracellular vesicles may facilitate the recycling of cytoplasmic content, which is engulfed in the vesicles and delivered to the main vacuole. Long-term starvation was characterized by a profound increase in cell size and morphological alterations in cellular ultrastructure. This study provides cellular and molecular basis for future ecophysiological assessment of natural E. huxleyi populations in oligotrophic regions. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  8. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

    Science.gov (United States)

    Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

    2012-03-01

    Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  10. Osteoblast recruitment routes in human cancellous bone remodeling

    DEFF Research Database (Denmark)

    Kristensen, Helene Bjørg; Andersen, Thomas Levin; Marcussen, Niels

    2014-01-01

    It is commonly proposed that bone forming osteoblasts recruited during bone remodeling originate from bone marrow perivascular cells, bone remodeling compartment canopy cells, or bone lining cells. However, an assessment of osteoblast recruitment during adult human cancellous bone remodeling...... is lacking. We addressed this question by quantifying cell densities, cell proliferation, osteoblast differentiation markers, and capillaries in human iliac crest biopsy specimens. We found that recruitment occurs on both reversal and bone-forming surfaces, as shown by the cell density and osterix levels...

  11. Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma

    Science.gov (United States)

    Klingbeil, E. C.; Hew, K. M.; Nygaard, U. C.; Nadeau, K. C.

    2014-01-01

    Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID:24760221

  12. Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling

    Directory of Open Access Journals (Sweden)

    Maricica Pacurari

    2015-01-01

    Full Text Available MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS- mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling.

  13. Circulating NOS3 modulates left ventricular remodeling following reperfused myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Simone Gorressen

    Full Text Available Nitric oxide (NO is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3. We have shown that NO protects against myocardial ischemia/reperfusion (I/R injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+ or in both, blood cells and vascular endothelium (BC+/EC+. Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.Three weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5 and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5 were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001 and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01 compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16. Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001 compared to BC+/EC+ (15.9±0.5; n = 16, and increased collagen type I and III subtypes

  14. 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

  15. Oscillation of Angiogenesis with Vascular Dropout in Diabetic Retinopathy by VESsel GENeration Analysis (VESGEN)

    Science.gov (United States)

    Parsons-Wingerter, Patricia; Radbakrishnan, Krisbnan; Vickerman, Mary B.; Kaiser, Peter K.

    2010-01-01

    PURPOSE. Vascular dropout and angiogenesis are hallmarks of the progression of diabetic retinopathy (DR). However, current evaluation of DR relies on grading of secondary vascular effects, such as microaneurysms and hemorrhages, by clinical examination instead of by evaluation of actual vascular changes. The purpose of this study was to map and quantify vascular changes during progression of DR by VESsel GENeration Analysis (VESGEN). METHODS. In this prospective cross-sectional study, 15 eyes with DR were evaluated with fluorescein angiography (FA) and color fundus photography, and were graded using modified Early Treatment Diabetic Retinopathy Study criteria. FA images were separated by semiautomatic image processing into arterial and venous trees. Vessel length density (L(sub v)), number density (N(sub v)), and diameter (D(sub v)) were analyzed in a masked fashion with VESGEN software. Each vascular tree was automatically segmented into branching generations (G(sub 1)...G(sub 8) or G(sub 9)) by vessel diameter and branching. Vascular remodeling status (VRS) for N(sub v) and L(sub v) was graded 1 to 4 for increasing severity of vascular change. RESULTS. By N(sub v) and L(sub v), VRS correlated significantly with the independent clinical diagnosis of mild to proliferative DR (13/15 eyes). N(sub v) and L(sub v) of smaller vessels (G(sub >=6) increased from VRS1 to VRS2 by 2.4 X and 1.6 X, decreased from VRS2 to VRS3 by 0.4 X and 0.6X, and increased from VRS3 to VRS4 by 1.7 X and 1.5 X (P dropout were dominated first by remodeling of arteries and subsequently by veins.

  16. Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance

    Directory of Open Access Journals (Sweden)

    E.R. Parra

    2012-07-01

    Full Text Available In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1 and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF. Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci, severe (mural fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.

  17. Redundancy of IL-1 Isoform Signaling and Its Implications for Arterial Remodeling.

    Directory of Open Access Journals (Sweden)

    Marina Beltrami-Moreira

    Full Text Available Mice deficient in IL-1 receptor 1 (hence unresponsive to both IL-1 isoforms α and β have impaired expansive arterial remodeling due to diminished expression of matrix-degrading enzymes, especially MMP-3. Emergence of IL-1 as a target in cardiovascular disease prompted the investigation of the redundancy of IL-1α and IL-1β in the induction of MMP-3 and other matrix-remodeling enzymes in human cells.Human primary vascular smooth muscle cells (VSMCs and carotid endarterectomy specimens were stimulated with equimolar concentrations of IL-1α or IL-1β and analyzed protease expression by immunoblot and ELISA. Either IL-1α or IL-1β increased the expression of pro-MMP-3 in VSMCs, facilitated VSMC migration through Matrigel, and induced MMP-3 production in specimens from atheromatous plaques. VSMCs also secreted MMP-1 and Cathepsin S (CatS upon stimulation with IL-1α or IL-1β. IL-1 isoforms similarly increased MMP-1 and MMP-9 expression in carotid endarterectomy specimens. We examined the expression of MMP-3 and IL-1 isoforms by immunostaining of carotid atheromata, calculated the % positive areas, and tested associations by linear regression. MMP-3 colocalized with IL-1 isoforms in atheromata. MMP-3+ area in plaques positively associated with IL-1α+ (R2 = 0.61, P<0.001 and with IL-1β + areas (R2 = 0.68, P<0.001. MMP-3+ area within atheroma also associated with CD68+ area, but not with α-smooth muscle actin area.Either IL-1α or IL-1β can induce the expression of enzymes implicated in remodeling of the arterial extracellular matrix, and facilitate human VSMC migration in vitro. Human atheromata contain both IL-1 isoforms in association with immunoreactive MMP-3. This redundancy of IL-1 isoforms suggests that selective blocking of one IL-1 isoform should not impair expansive arterial remodeling, a finding with important clinical implications for therapeutic targeting of IL-1 in atherosclerosis.

  18. 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.

  19. 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. 

  20. 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

  1. DOPAMINE EFFECT ON CARDIAC REMODELING IN EXPERIMENT

    Directory of Open Access Journals (Sweden)

    V. R. Veber

    2009-01-01

    Full Text Available Aim. To study morphologic changes in myocardium of Wistar rats caused by single and long term dopamine administration.Methods. In acute study dopamine 10 mkg/kg was administrated to 15 rats by a single intraperitoneal injection. The material was taken in 2, 6, 24 hours and in 1 month after drug administration. In chronic study dopamine 10 mkg/kg was administrated to 15 rats 3 times a day by intraperitoneal injections during 2 weeks. The material was taken just after the drug administration was stopped and in 1 month of animals keeping without stress and drug influences. Control group included 15 rats comparable with experimental animals in age and weight. They were keeped without stress and drug influences. Morphometric parameters of left and right ventricles were evaluated as well as density of cardiomyocytes, collagen, vessels and volume of extracellular space.Results. The enlargement of cardiac fibrosis is found both in acute, and in chronic study. In acute study cardiac fibrosis was located mainly in a right ventricle. In chronic study cardiac fibrosis was located in both ventricles, but also mainly in a right one.Conclusion. Significant morphological «asynchronism» of the left and right ventricles remodeling requires elaboration of methods of myocardium protection and cardiac function control during dopamine administration. 

  2. Book Review: Remodeling GT once again

    Directory of Open Access Journals (Sweden)

    Alvita Nathaniel

    2014-06-01

    Full Text Available Barry Gibson and Jan Hartman (2014: Rediscovering Grounded Theory London: Sage In their book entitled Rediscovering Grounded Theory, Barry Gibson and Jan Hartman (2014 aim to present grounded theory in a new way with the intention of “forward looking preservation” (p. 237. They claim that Rediscovery is an outcome of many conversations in a London pub over the last eight years. The authors tackle both method and methodology as they meticulously describe the context of The Discovery of Grounded Theory (Glaser & Strauss, 1967 and take an authoritative stand on many of the controversies surrounding remodeling of the method in recent years. Rediscovering also includes substantial how-to sections corresponding to chapters in Glaser’s Theoretical Sensitivity (1978. Rediscovery adds explanatory depth in its discussion of the context of grounded theory, but fails to keep many of its promises. Rediscovery is far reaching. Included in the first part are chapters entitled, What Kind of Theory is Grounded Theory, Constructivism in Grounded Theory, Disentangling Concepts and Categories in Grounded Theory, and Coding in Grounded Theory. These chapters describe the context of the method, discuss the controversies, and present Gibson and Hardman’s positions on contentious issues. The second part of the book consists of chapters that aim to help grounded theorists with procedures such as developing theoretical sensitivity, theoretical sampling, coding, memoing, and writing theory. To their credit, the authors continually acknowledge the originators of the method.

  3. Matrix remodeling between cells and cellular interactions with collagen bundle

    Science.gov (United States)

    Kim, Jihan; Sun, Bo

    When cells are surrounded by complex environment, they continuously probe and interact with it by applying cellular traction forces. As cells apply traction forces, they can sense rigidity of their local environment and remodel the matrix microstructure simultaneously. Previous study shows that single human carcinoma cell (MDA-MB-231) remodeled its surrounding extracellular matrix (ECM) and the matrix remodeling was reversible. In this study we examined the matrix microstructure between cells and cellular interaction between them using quantitative confocal microscopy. The result shows that the matrix microstructure is the most significantly remodeled between cells consisting of aligned, and densified collagen fibers (collagen bundle)., the result shows that collagen bundle is irreversible and significantly change micromechanics of ECM around the bundle. We further examined cellular interaction with collagen bundle by analyzing dynamics of actin and talin formation along with the direction of bundle. Lastly, we analyzed dynamics of cellular protrusion and migrating direction of cells along the bundle.

  4. [Hormones and osteoporosis update. Regulation of bone remodeling by neuropeptides and neurotransmitters].

    Science.gov (United States)

    Takeda, Shu

    2009-07-01

    From the discovery of the regulation of bone remodelling by leptin, much attention has been focused on neurogenic control of bone remodelling. Various hypothalamic neuropeptides, which are involved in appetite regulation, are now revealed to be important regulators of bone remodelling. More recently, neurotransmitters, such as serotonin or catecholamines, are proven to be bone remodelling regulators.

  5. 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

  6. 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.

  7. 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

  8. Endothelial remodelling and intracellular calcium machinery.

    Science.gov (United States)

    Moccia, F; Tanzi, F; Munaron, L

    2014-05-01

    Rather being an inert barrier between vessel lumen and surrounding tissues, vascular endothelium plays a key role in the maintenance of cardiovascular homeostasis. The de-endothelialization of blood vessels is regarded as the early event that results in the onset of severe vascular disorders, including atherosclerosis, acute myocardial infarction, brain stroke, and aortic aneurysm. Restoration of the endothelial lining may be accomplished by the activation of neighbouring endothelial cells (ECs) freed by contact inhibition and by circulating endothelial progenitor cells (EPCs). Intracellular Ca(2+) signalling is essential to promote wound healing: however, the molecular underpinnings of the Ca(2+) response to injury are yet to be fully elucidated. Similarly, the components of the Ca(2+) toolkit that drive EPC incorporation into denuded vessels are far from being fully elucidated. The present review will survey the current knowledge on the role of Ca(2+) signalling in endothelial repair and in EPC activation. We propose that endothelial regeneration might be boosted by intraluminal release of specific Ca(2+) channel agonists or by gene transfer strategies aiming to enhance the expression of the most suitable Ca(2+) channels at the wound site. In this view, connexin (Cx) channels/hemichannels and store-operated Ca(2+) entry (SOCE) stand amid the most proper routes to therapeutically induce the regrowth of denuded vessels. Cx stimulation might trigger the proliferative and migratory behaviour of ECs facing the lesion site, whereas activation of SOCE is likely to favour EPC homing to the wounded vessel.

  9. Cell Matrix Remodeling Ability Shown by Image Spatial Correlation

    Science.gov (United States)

    Chiu, Chi-Li; Digman, Michelle A.; Gratton, Enrico

    2013-01-01

    Extracellular matrix (ECM) remodeling is a critical step of many biological and pathological processes. However, most of the studies to date lack a quantitative method to measure ECM remodeling at a scale comparable to cell size. Here, we applied image spatial correlation to collagen second harmonic generation (SHG) images to quantitatively evaluate the degree of collagen remodeling by cells. We propose a simple statistical method based on spatial correlation functions to determine the size of high collagen density area around cells. We applied our method to measure collagen remodeling by two breast cancer cell lines (MDA-MB-231 and MCF-7), which display different degrees of invasiveness, and a fibroblast cell line (NIH/3T3). We found distinct collagen compaction levels of these three cell lines by applying the spatial correlation method, indicating different collagen remodeling ability. Furthermore, we quantitatively measured the effect of Latrunculin B and Marimastat on MDA-MB-231 cell line collagen remodeling ability and showed that significant collagen compaction level decreases with these treatments. PMID:23935614

  10. Remodelling Marketing Communications in an Internet Environment.

    Science.gov (United States)

    Rowley, Jennifer

    2001-01-01

    Argues that the Internet demands a significant review of approaches to marketing communications, or promotion, as both the strategic and tactical levels. Highlights include electronic business and electronic commerce; comparing organizational and consumer markets; service development; objectives of marketing communications; and questions for…

  11. Modification of a Volume-Overload Heart Failure Model to Track Myocardial Remodeling and Device-Related Reverse Remodeling

    Science.gov (United States)

    Tuzun, Egemen; Bick, Roger; Kadipasaoglu, Cihan; Conger, Jeffrey L.; Poindexter, Brian J.; Gregoric, Igor D.; Frazier, O. H.; Towbin, Jeffrey A.; Radovancevic, Branislav

    2011-01-01

    Purpose. To provide an ovine model of ventricular remodeling and reverse remodeling by creating congestive heart failure (CHF) and then treating it by implanting a left ventricular assist device (LVAD). Methods. We induced volume-overload heart failure in 2 sheep; 20 weeks later, we implanted an LVAD and assessed recovery 11 weeks thereafter. We examined changes in histologic and hemodynamic data and levels of cellular markers of CHF. Results. After CHF induction, we found increases in LV end-diastolic pressure, LV systolic and diastolic dimensions, wall thickness, left atrial diameter, and atrial natriuretic protein (ANP) and endothelin-1 (ET-1) levels; β-adrenergic receptor (BAR) and dystrophin expression decreased markedly. Biopsies confirmed LV remodeling. After LVAD support, LV systolic and diastolic dimensions, wall thickness, and mass, and ANP and ET-1 levels decreased. Histopathologic and hemodynamic markers improved, and BAR and dystrophin expression normalized. Conclusions. We describe a successful sheep model for ventricular and reverse remodeling. PMID:22347659

  12. Mutation of neuron-specific chromatin remodeling subunit BAF53b : rescue of plasticity and memory by manipulating actin remodeling

    NARCIS (Netherlands)

    Vogel Ciernia, Annie; Kramár, Enikö A; Matheos, Dina P; Havekes, Robbert; Hemstedt, Thekla J; Magnan, Christophe N; Sakata, Keith; Tran, Ashley; Azzawi, Soraya; Lopez, Alberto; Dang, Richard; Wang, Weisheng; Trieu, Brian; Tong, Joyce; Barrett, Ruth M; Post, Rebecca J; Baldi, Pierre; Abel, Ted; Lynch, Gary; Wood, Marcelo A

    Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes

  13. Side-to-side sutureless vascular anastomosis with magnets.

    Science.gov (United States)

    Erdmann, Detlev; Sweis, Ranya; Heitmann, Christoph; Yasui, Koji; Olbrich, Kevin C; Levin, L Scott; Sharkawy, A Adam; Klitzman, Bruce

    2004-09-01

    Abbe and Payr introduced vascular techniques and devices to facilitate vessel anastomosis over a century ago. Obora published the idea of a sutureless vascular anastomosis with use of magnetic rings in 1978. The purpose of this study was to assess the performance of a new magnetic device to perform a side-to-side arteriovenous anastomosis in a dog model. Male fox hounds (25 kg) were treated preoperatively and daily postoperatively with clopidogrel bisulfate (Plavix) and aspirin. The femoral artery and vein were exposed unilaterally in 3 dogs and bilaterally in 4 dogs (n = 11 anastomoses). A 4-mm arteriotomy was performed, and 1 oval magnet 0.5 mm thick was inserted into the lumen of the artery and a second magnet was applied external to the artery, compressing and stabilizing the arterial wall to create a magnetic port. An identical venous magnetic port was created with another pair of oval magnets. When the 2 ports were allowed to approach each other, they self-aligned and magnetically coupled to complete the arteriovenous anastomosis. Patency was assessed for the first hour with direct observation, again after 9 weeks with duplex ultrasound scanning, and at 10 weeks under direct open observation. The anastomoses were explanted after 10 weeks. Hydrodynamic resistance was measured ex vivo on the final 8 anastomoses by measuring the pressure drop across an anastomosis with a known flow rate. After implantation, very high flow created visible turbulence and palpable vibration. All 11 anastomoses were patent under direct observation and palpation. Ten of 11 anastomoses were clearly patent on duplex scans, and patency of 1 anastomosis was questionable. Hydrodynamic resistance averaged 0.73 +/- 0.33 mm Hg min/mL (mean +/- SEM). Vascular anastomoses performed with magnets demonstrated feasibility; exhibited 100% patency after 10 weeks in a dog arteriovenous shunt model; lacked apparent aneurysm or other potentially catastrophic failure; demonstrated remodeling of the

  14. Barriers to franchise initiation for general remodelers in U.S. remodeling industry: A non-franchisor perspective

    OpenAIRE

    Murray, B. C.

    2008-01-01

    The following report is an exploratory investigation into the barriers of franchise initiation for general contractors in the US remodeling industry. The applicability of theories used to describe why firms franchise is evaluated using secondary quantitative data. Further exploration is achieved by interviewing non-franchising, general remodelers classified as 'potential franchisors'. Overall, the outcomes suggest that franchisee recruitment is a perceived operational barrier by general remod...

  15. Cardiac remodeling indicators in adolescent athletes

    Directory of Open Access Journals (Sweden)

    Joaquim Castanheira

    Full Text Available Summary Objective: The idea that different sports and physical training type results in different cardiac adaptations has been widely accepted. However, this remodelling process among different sport modalities is still not fully understood. Thus, the current study aims to investigate the heart morphology variation associated with a set of different modalities characterized by distinct models of preparation and different methods and demands of training and completion. Method: The sample comprises 42 basketball players, 73 roller hockey players, 28 judo athletes and 21 swimmers. Anthropometry was assessed by a single and experienced anthropometrist and the same technician performed the echocardiographic exams. Analysis of variance was used to study age, body size and echocardiograph parameters as well as different sport athlete's comparison. Results: Basketball players are taller (F=23.448; p<0.001; ES-r=0.553, heavier (F=6.702; p<0.001; ES-r=0.334 and have a greater body surface area (F=11.896; p<0.001; ES-r=0.427. Basketball and hockey players have larger left auricle diameters compared with judo athletes (F=3.865; p=0.011; ES-r=0.316. Interventricular end-diastolic septal thickness (F=7.287; p<0.001; ES-r=0.347 and left ventricular posterior wall thickness (F=8.038; p<0.001; ES-r=0.362 of the judokas are smaller compared to the mean values of other sports participants. In addition, relative left parietal ventricular wall thickness is lower among swimmers compared with judokas (F=4.127; p=0.008; ES-r=0.268. Conclusion: The major contributors to changes in heart morphology are for the most part associated with sport-specific training and competition and the specific dynamics and adaptive mechanisms imposed by each sport.

  16. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    International Nuclear Information System (INIS)

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-01-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula’s material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element’s remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than

  17. GPR68 Senses Flow and Is Essential for Vascular Physiology.

    Science.gov (United States)

    Xu, Jie; Mathur, Jayanti; Vessières, Emilie; Hammack, Scott; Nonomura, Keiko; Favre, Julie; Grimaud, Linda; Petrus, Matt; Francisco, Allain; Li, Jingyuan; Lee, Van; Xiang, Fu-Li; Mainquist, James K; Cahalan, Stuart M; Orth, Anthony P; Walker, John R; Ma, Shang; Lukacs, Viktor; Bordone, Laura; Bandell, Michael; Laffitte, Bryan; Xu, Yan; Chien, Shu; Henrion, Daniel; Patapoutian, Ardem

    2018-04-19

    Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. A biodegradable vascularizing membrane: a feasibility study.

    Science.gov (United States)

    Kaushiva, Anchal; Turzhitsky, Vladimir M; Darmoc, Marissa; Backman, Vadim; Ameer, Guillermo A

    2007-09-01

    Regenerative medicine and in vivo biosensor applications require the formation of mature vascular networks for long-term success. This study investigated whether biodegradable porous membranes could induce the formation of a vascularized fibrous capsule and, if so, the effect of degradation kinetics on neovascularization. Poly(l-lactic acid) (PLLA) and poly(dl-lactic-co-glycolic) acid (PLGA) membranes were created by a solvent casting/salt leaching method. Specifically, PLLA, PLGA 75:25 and PLGA 50:50 polymers were used to vary degradation kinetics. The membranes were designed to have an average 60mum pore diameter, as this pore size has been shown to be optimal for inducing blood vessel formation around nondegradable polymer materials. Membrane samples were imaged by scanning electron microscopy at several time points during in vitro degradation to assess any changes in pore structure. The in vivo performance of the membranes was assessed in Sprague-Dawley rats by measuring vascularization within the fibrous capsule that forms adjacent to implants. The vascular density within 100microm of the membranes was compared with that seen in normal tissue, and to that surrounding the commercially available vascularizing membrane TheraCyte. The hemoglobin content of tissue containing the membranes was measured by four-dimensional elastic light scattering as a novel method to assess tissue perfusion. Results from this study show that slow-degrading membranes induce greater amounts of neovascularization and a thinner fibrous capsule relative to fast degrading membranes. These results may be due both to an initially increased number of macrophages surrounding the slower degrading membranes and to the maintenance of their initial pore structure.

  19. Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension.

    Science.gov (United States)

    Stenmark, Kurt R; Frid, Maria G; Graham, Brian B; Tuder, Rubin M

    2018-03-15

    Pulmonary hypertension (PH) is the end result of interaction between pulmonary vascular tone and a complex series of cellular and molecular events termed 'vascular remodelling'. The remodelling process, which can involve the entirety of pulmonary arterial vasculature, almost universally involves medial thickening, driven by increased numbers and hypertrophy of its principal cellular constituent, smooth muscle cells (SMCs). It is noted, however that SMCs comprise heterogeneous populations of cells, which can exhibit markedly different proliferative, inflammatory, and extracellular matrix production changes during remodelling. We further consider that these functional changes in SMCs of different phenotype and their role in PH are dynamic and may undergo significant changes over time (which we will refer to as cellular plasticity); no single property can account for the complexity of the contribution of SMC to pulmonary vascular remodelling. Thus, the approaches used to pharmacologically manipulate PH by targeting the SMC phenotype(s) must take into account processes that underlie dominant phenotypes that drive the disease. We present evidence for time- and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed 'SMCs' may arise from many origins, including endothelial cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro-inflammatory phenotype by SMC that is essential

  20. Electronic plants

    Science.gov (United States)

    Stavrinidou, Eleni; Gabrielsson, Roger; Gomez, Eliot; Crispin, Xavier; Nilsson, Ove; Simon, Daniel T.; Berggren, Magnus

    2015-01-01

    The roots, stems, leaves, and vascular circuitry of higher plants are responsible for conveying the chemical signals that regulate growth and functions. From a certain perspective, these features are analogous to the contacts, interconnections, devices, and wires of discrete and integrated electronic circuits. Although many attempts have been made to augment plant function with electroactive materials, plants’ “circuitry” has never been directly merged with electronics. We report analog and digital organic electronic circuits and devices manufactured in living plants. The four key components of a circuit have been achieved using the xylem, leaves, veins, and signals of the plant as the template and integral part of the circuit elements and functions. With integrated and distributed electronics in plants, one can envisage a range of applications including precision recording and regulation of physiology, energy harvesting from photosynthesis, and alternatives to genetic modification for plant optimization. PMID:26702448

  1. 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

  2. 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.

  3. Increase in Vascular Injury of Sodium Overloaded Mice May be Related to Vascular Angiotensin Modulation.

    Directory of Open Access Journals (Sweden)

    Cintia Taniguti Lima

    Full Text Available This study aimed to analyzing the effect of chronic sodium overload upon carotid and femoral injury, and its relation to vascular angiotensin modulation. Male C57Bl6 mice were divided in: control (cont, receiving 1% NaCl solution for 2 weeks (salt-2 or 12 weeks (salt-12. Two-weeks before the end of the study, a 2mm catheter was implanted around the left femoral and carotid arteries to induce injury. Blood pressure (BP and heart rate (HR were measured at the end of the study by tail plethysmography. Arteries were collected and prepared for histological analysis to determine arterial thickening and perivascular collagen deposition. Angiotensin II and Ang(1-7 were quantified in fresh arteries using the HPLC method. There were no differences in body weight, BP and HR. Intima/media ratio had a similar increase in both injured arteries of cont and salt-2 mice, but a more pronounced increase was observed in salt-12 mice (31.1±6%. On the other hand, sodium overload modified perivascular collagen deposition, increasing thick fibers (cont: 0.5%; salt-2: 3.4%; salt-12: 0.6% and decreasing thin fibers (cont: 7.4%; salt-2: 0.5%; salt-12: 6.8% in non-injured arteries. Injured arteries presented similar collagen fiber distribution. Angiotensin quantification showed increased Ang(1-7 in salt treated mice (salt-2: +72%; salt-12: +45% with a concomitant decrease in Ang II (salt-2: -54%; salt-12: -60%. Vascular injury increased significantly Ang(1-7 in salt-12 mice (+80%, maintaining Ang II reduction similar to that of a non-injured artery. The lack of changes in BP and HR suggests that the structural changes observed may be due to non-hemodynamic mechanisms such as local renin-angiotensin system. Collagen evaluation suggests that sodium overload induces time-related changes in vascular remodeling. The increase of artery injury with concomitant increase in Ang(1-7 in 12-week treated mice shows a direct association between the duration of salt treatment and the

  4. 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.

  5. Role of MMP-12 on tissue remodeling at early stage of radiation-induced pulmonary injury

    International Nuclear Information System (INIS)

    Li Ming; Song Liangwen; Diao Ruiying; Wang Shaoxia; Xu Xinping; Luo Qingliang

    2008-01-01

    Objective: To explore the role of MMP-12 on tissue remodeling at early stage of radiation- induced pulmonary injury. Methods: Wistar rats irradiated by 60 Co γ-rays to the whole lungs were sacrificed at 1, 2, 4 weeks. MMP-12 mRNA expression was detected by RT-PCR. MMP-2, MMP-9, MMP-12 activities were determined by zymography. The degradation and collapse of elastin were determined by tissue elastin particular staining; the 'cross talking' phenomenon between alveolar type II cells and mesenchymal cells was observed under electron microscope; the expression of TGF-β1 and TNF-α in BALF was detected by ELISA. The expression of α-SMA was determined by immunohistochemistry. Results: The mRNA expression of MMP-12 displayed a significant elevation at 1, 2, 4 weeks after irradiation. MMP-12 activity increased at 2, 4 weeks after irradiation. Elastin began to degrade and collapse at 1 week, which became worst 4 weeks after irradiation. The cross talking phenomenon was found under electron microscope. The expression of TGF-β1, TNF-α and α-SMA was increased gradually as time elapse after irradiation. Conclusions: 60 Co γ-ray irradiation can promote pulmonary MMP-12 expression, initiate pulmonary tissue remodeling by degradation of elastin, and make the pulmonary injury develop towards pulmonary fibrosis eventually. (authors)

  6. Enhanced Prevalence of Plasmatic Soluble MHC Class I Chain-Related Molecule in Vascular Pregnancy Diseases

    Directory of Open Access Journals (Sweden)

    Jean Baptiste Haumonte

    2014-01-01

    Full Text Available The major histocompatibility complex class I related chain (MIC is a stress-inducible protein modulating the function of immune natural killer (NK cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC may reflect immune disorders associated to vascular pregnancy diseases (VPD. sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32% than in normal term-matched pregnancies (1.6%, P<0.0001, with highest prevalence in intrauterine fetal death (IUDF, 44% and vascular intrauterine growth restriction (IUGR, 39%. sMIC levels were higher in preeclampsia (PE than in IUFD (P<0.01 and vascular IUGR (P<0.05. sMIC detection was associated with bilateral early diastolic uterine notches (P=0.037, thrombocytopenia (P=0.03, and high proteinuria (P=0.03 in PE and with the vascular etiology of IUGR (P=0.0038. Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.

  7. Critical role of nucleotide-binding oligomerization domain-like receptor 3 in vascular repair

    Energy Technology Data Exchange (ETDEWEB)

    Schlaweck, Sebastian; Zimmer, Sebastian; Struck, Rafael [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Bartok, Eva [Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Werner, Nikos [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Bauernfeind, Franz [Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Latz, Eicke [Institute of Innate Immunity, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Nickenig, Georg [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Hornung, Veit [Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany); Ghanem, Alexander, E-mail: ghanem@uni-bonn.de [Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn (Germany)

    2011-08-05

    Highlights: {yields} NLRP3 is not required for systemic cardiovascular function in healthy mice. {yields} NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and that it does not alter peripheral differential blood counts. {yields} NLRP3 is critical in neointima formation following vascular injury. -- Abstract: Vascular remodeling characterized by hyperproliferative neointima formation is an unfavorable repair process that is triggered by vascular damage. This process is characterized by an increased local inflammatory and proliferative response that critically involves the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}). IL-1{beta} is expressed and cytosolically retained as a procytokine that requires additional processing prior to exerting its pro-inflammatory function. Maturation and release of pro IL-1{beta} is governed by a cytosolic protein scaffold that is known as the inflammasome. Here we show that NLRP3 (NOD-like receptor family, pryin domain containing 3), an important activating component of the inflammasome, is involved in neointima formation after vascular injury. NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and does not alter peripheral differential blood counts. However, neointima development following wire injury of the carotid artery was significantly decreased in NLRP3-deficient mice as compared to wild-type controls. In all, NLRP3 plays a non-redundant role in vascular damage mediated neointima formation. Our data establish NLRP3 as a key player in the response to vascular damage, which could open new avenues to therapeutic intervention.

  8. Critical role of nucleotide-binding oligomerization domain-like receptor 3 in vascular repair

    International Nuclear Information System (INIS)

    Schlaweck, Sebastian; Zimmer, Sebastian; Struck, Rafael; Bartok, Eva; Werner, Nikos; Bauernfeind, Franz; Latz, Eicke; Nickenig, Georg; Hornung, Veit; Ghanem, Alexander

    2011-01-01

    Highlights: → NLRP3 is not required for systemic cardiovascular function in healthy mice. → NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and that it does not alter peripheral differential blood counts. → NLRP3 is critical in neointima formation following vascular injury. -- Abstract: Vascular remodeling characterized by hyperproliferative neointima formation is an unfavorable repair process that is triggered by vascular damage. This process is characterized by an increased local inflammatory and proliferative response that critically involves the pro-inflammatory cytokine interleukin-1β (IL-1β). IL-1β is expressed and cytosolically retained as a procytokine that requires additional processing prior to exerting its pro-inflammatory function. Maturation and release of pro IL-1β is governed by a cytosolic protein scaffold that is known as the inflammasome. Here we show that NLRP3 (NOD-like receptor family, pryin domain containing 3), an important activating component of the inflammasome, is involved in neointima formation after vascular injury. NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and does not alter peripheral differential blood counts. However, neointima development following wire injury of the carotid artery was significantly decreased in NLRP3-deficient mice as compared to wild-type controls. In all, NLRP3 plays a non-redundant role in vascular damage mediated neointima formation. Our data establish NLRP3 as a key player in the response to vascular damage, which could open new avenues to therapeutic intervention.

  9. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders

    Directory of Open Access Journals (Sweden)

    Alberto J Lopez

    2015-04-01

    Full Text Available It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, schizophrenia, and Autism Spectrum Disorder. Together, these human developmental and intellectual disability disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development.

  10. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders.

    Science.gov (United States)

    López, Alberto J; Wood, Marcelo A

    2015-01-01

    It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability (ID) disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF) complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), schizophrenia, and Autism Spectrum Disorder (ASD). Together, these human developmental and ID disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and ID disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development.

  11. Review of gestational diabetes mellitus effects on vascular structure and function.

    Science.gov (United States)

    Jensen, Louise A; Chik, Constance L; Ryan, Edmond A

    2016-05-01

    Vascular dysfunction has been described in women with a history of gestational diabetes mellitus. Furthermore, previous gestational diabetes mellitus increases the risk of developing Type 2 diabetes mellitus, a risk factor for cardiovascular disease. Factors contributing to vascular changes remain uncertain. The aim of this review was to summarize vascular structure and function changes found to occur in women with previous gestational diabetes mellitus and to identify factors that contribute to vascular dysfunction. A systematic search of electronic databases yielded 15 publications from 1998 to March 2014 that met the inclusion criteria. Our review confirmed that previous gestational diabetes mellitus contributes to vascular dysfunction, and the most consistent risk factor associated with previous gestational diabetes mellitus and vascular dysfunction was elevated body mass index. Heterogeneity existed across studies in determining the relationship of glycaemic levels and insulin resistance to vascular dysfunction. © The Author(s) 2016.

  12. Vascular endothelial dysfunction in β-thalassemia occurs despite increased eNOS expression and preserved vascular smooth muscle cell reactivity to NO.

    Directory of Open Access Journals (Sweden)

    Ekatherina Stoyanova

    Full Text Available The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO. While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression.

  13. Correlation between genetic polymorphism of matrix metalloproteinase-9 in patients with coronary artery disease and cardiac remodeling.

    Science.gov (United States)

    Yu, Qibin; Li, Hanmei; Li, Linlin; Wang, Shaoye; Wu, Yongbo

    2015-01-01

    To explore the correlation between genetic polymorphism of matrix metalloproteinase-9 (MMP-9) in patients with coronary artery disease (CAD) and cardiac remodeling. A total of 272 subjects who received coronary angiography in our hospital from July 2008 to September 2013 were selected, including 172 CAD patients (CAD group) and another 100 ones (control group). Both groups were subjected to MMP-9 and ultrasonic detections to determine vascular remodeling and atherosclerotic plaques. C1562G polymorphism of MMP-9 gene was detected, and correlation with vascular remodeling and atherosclerotic plaque was analyzed. Serum MMP-9 level of CAD group (330.87±50.39 ng/ml) was significantly higher than that of control group (134.87±34.02 ng/ml) (P<0.05). Compared with control group, CAD group had significantly higher intima-media thickness, and significantly lower systolic peak velocity, mean systolic velocity and end-diastolic velocity (P<0.05). Total area of stenotic blood vessels was 67.34±22.98 mm(2), while that of control blood vessels was 64.00±20.83 mm(2). G/G, G/C and C/C genotype frequencies of MMP-9 differed significantly in the two groups (P<0.05). G and C allele frequencies of CAD group (70.9% and 29.1%) were significantly different from those of control group (50.0% and 50.0%) (P<0.05). G/G, G/C and C/C genotypes were manifested as lipid-rich, fibrous and calcified or ulcerated plaques respectively. Total area of stenotic blood vessels of G/G genotype significantly exceeded those of G/C and C/C genotypes (P<0.05), whereas the latter two had no significant differences. CAD promoted 1562C-G transformation of MMP-9 gene into genetic polymorphism, thus facilitating arterial remodeling and increasing unstable atherosclerotic plaques.

  14. Morphological and biomechanical remodeling of the hepatic portal vein in a swine model of portal hypertension.

    Science.gov (United States)

    He, Xi-Ju; Huang, Tie-Zhu; Wang, Pei-Jun; Peng, Xing-Chun; Li, Wen-Chun; Wang, Jun; Tang, Jie; Feng, Na; Yu, Ming-Hua

    2012-02-01

    To obtain the morphological and biomechanical remodeling of portal veins in swine with portal hypertension (PHT), so as to provide some mechanical references and theoretical basis for clinical practice about PHT. Twenty white pigs were used in this study, 14 of them were subjected to both carbon tetrachloride- and pentobarbital-containing diet to induce experimental liver cirrhosis and PHT, and the remaining animals served as the normal controls. The morphological remodeling of portal veins was observed. Endothelial nitric oxide synthase expression profile in the vessel wall was assessed at both mRNA and protein level. The biomechanical changes of the hepatic portal veins were evaluated through assessing the following indicators: the incremental elastic modulus, pressure-strain elastic modulus, volume elastic modulus, and the incremental compliance. The swine PHT model was successfully established. The percentages for the microstructural components and the histological data significantly changed in the experimental group. Endothelial nitric oxide synthase expression was significantly downregulated in the portal veins of the experimental group. Three incremental elastic moduli (the incremental elastic modulus, pressure-strain elastic modulus, and volume elastic modulus) of the portal veins from PHT animals were significantly larger than those of the controls (P portal vein decreased. Our study suggests that the morphological and biomechanical properties of swine hepatic portal veins change significantly during the PHT process, which may play a critical role in the development of PHT and serve as potential therapeutic targets during clinical practice. Copyright © 2012 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.

  15. Lentil-based diets attenuate hypertension and large-artery remodelling in spontaneously hypertensive rats.

    Science.gov (United States)

    Hanson, Matthew G; Zahradka, Peter; Taylor, Carla G

    2014-02-01

    Hypertension is a major risk factor for CVD, the leading cause of mortality worldwide. The prevalence of hypertension is expected to continue increasing, and current pharmacological treatments cannot alleviate all the associated problems. Pulse crops have been touted as a general health food and are now being studied for their possible effects on several disease states including hypertension, obesity and diabetes. In the present study, 15-week-old spontaneously hypertensive rats (SHR) were fed diets containing 30% w/w beans, peas, lentils, chickpeas, or mixed pulses or a pulse-free control diet for 4 weeks. Normotensive Wistar-Kyoto (WKY) rats were placed on a control diet. Pulse wave velocity (PWV) was measured weekly, while blood pressure (BP) was measured at baseline and week 4. Fasting serum obtained in week 4 of the study was analysed for circulating lipids. A histological analysis was carried out on aortic sections to determine vascular geometry. Of all the pulse varieties studied, lentils were found to be able to attenuate the rise in BP in the SHR model (P< 0·05). Lentils were able to decrease the media:lumen ratio and media width of the aorta. The total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol levels of rats fed the pulse-based diets were found to be lower when compared with those of the WKY rat and SHR controls (P< 0·05). Although all pulses reduced circulating TC and LDL-C levels in the SHR, only lentils significantly reduced the rise in BP and large-artery remodelling in the SHR, but had no effect on PWV. These results indicate that the effects of lentils on arterial remodelling and BP in the SHR are independent of circulating LDL-C levels.

  16. Neural circuit rewiring: insights from DD synapse remodeling.

    Science.gov (United States)

    Kurup, Naina; Jin, Yishi

    2016-01-01

    Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

  17. Cardiac and vascular malformations

    International Nuclear Information System (INIS)

    Ley, S.; Ley-Zaporozhan, J.

    2015-01-01

    Malformations of the heart and great vessels show a high degree of variation. There are numerous variants and defects with only few clinical manifestations and are only detected by chance, such as a persistent left superior vena cava or a partial anomalous pulmonary venous connection. Other cardiovascular malformations are manifested directly after birth and need prompt mostly surgical interventions. At this point in time echocardiography is the diagnostic modality of choice for morphological and functional characterization of malformations. Additional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) is only required in a minority of cases. If so, the small anatomical structures, the physiological tachycardia and tachypnea are a challenge for imaging modalities and strategies. This review article presents the most frequent vascular, cardiac and complex cardiovascular malformations independent of the first line diagnostic imaging modality. (orig.) [de

  18. Airway remodeling and its reversibility in equine asthma

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Lavoie

    2017-06-01

    Full Text Available Despite effective therapies for controlling its clinical manifestations, human asthma remains an incurable disease. It is now recognized that inflammation induced structural changes (remodeling of the airways are responsible for the progressive loss of lung function in asthmatic patients. However, the peripheral airways, where most of the remodeling occurs in severe asthmatic patients, cannot be safely sampled in humans, and therefore, little is known of the effects of current therapies at reversing the established asthmatic remodeling, especially those occurring in the peripheral airways. Animal models have been studied to unravel etiological, immunopathological, and genetic attributes leading to asthma. However, experiments in which the disease is artificially induced have been shown to have limited translational potential for humans. To the contrary, horses naturally suffer from an asthma-like condition which shares marked similarities with human asthma making this model unique to investigate the kinetics, reversibility, as well as the physiological consequences of tissue remodeling (Bullone and Lavoie 2015. We reported an increased deposition of smooth muscle, collagen and elastic fibers in the peripheral airways of affected horses, which was correlated with the lung function (Herszberg et al., 2006; Setlakwe et al., 2014. The airway subepithelial collagen depositions were almost completely reversed with 6 to 12 months of treatment with either antigen avoidance or inhaled corticosteroids (ICS administration, and there was a modest (30% on average decrease in airway smooth muscle (Leclere et al., 2011. A recent study also found that ICS combined with long-acting ß2-agonists drugs (LABA and ICS monotherapy similarly induced a 30% decrease of the airway smooth muscle mass at 3 months (Buollone, 2017. However, only ICS/LABA and antigen avoidance decreased airway luminal neutrophilia. The findings indicate the enhance therapeutic effect of ICS

  19. CIRSE Vascular Closure Device Registry

    NARCIS (Netherlands)

    Reekers, Jim A.; Müller-Hülsbeck, Stefan; Libicher, Martin; Atar, Eli; Trentmann, Jens; Goffette, Pierre; Borggrefe, Jan; Zeleňák, Kamil; Hooijboer, Pieter; Belli, Anna-Maria

    2011-01-01

    Vascular closure devices are routinely used after many vascular interventional radiology procedures. However, there have been no major multicenter studies to assess the safety and effectiveness of the routine use of closure devices in interventional radiology. The CIRSE registry of closure devices

  20. Dynamic adaption of vascular morphology

    DEFF Research Database (Denmark)

    Okkels, Fridolin; Jacobsen, Jens Christian Brings

    2012-01-01

    The structure of vascular networks adapts continuously to meet changes in demand of the surrounding tissue. Most of the known vascular adaptation mechanisms are based on local reactions to local stimuli such as pressure and flow, which in turn reflects influence from the surrounding tissue. Here ...

  1. Diagnostic criteria for vascular dementia

    NARCIS (Netherlands)

    Scheltens, P.; Hijdra, A. H.

    1998-01-01

    The term vascular dementia implies the presence of a clinical syndrome (dementia) caused by, or at least assumed to be caused by, a specific disorder (cerebrovascular disease). In this review, the various sets of criteria used to define vascular dementia are outlined. The various sets of criteria

  2. The vascular secret of Klotho

    DEFF Research Database (Denmark)

    Lewin, Ewa; Olgaard, Klaus

    2015-01-01

    Klotho is an evolutionarily highly conserved protein related to longevity. Increasing evidence of a vascular protecting effect of the Klotho protein has emerged and might be important for future treatments of uremic vascular calcification. It is still disputed whether Klotho is locally expressed ...

  3. [Experimental therapy of cardiac remodeling with quercetin-containing drugs].

    Science.gov (United States)

    Kuzmenko, M A; Pavlyuchenko, V B; Tumanovskaya, L V; Dosenko, V E; Moybenko, A A

    2013-01-01

    It was shown that continuous beta-adrenergic hyperstimulation resulted in cardiac function disturbances and fibrosis of cardiac tissue. Treatment with quercetin-containing drugs, particularly, water-soluble corvitin and tableted quertin exerted favourable effect on cardiac hemodynamics, normalized systolic and diastolic function in cardiac remodeling, induced by sustained beta-adrenergic stimulation. It was estimated that conducted experimental therapy limited cardiac fibrosis area almost three-fold, that could be associated with first and foremost improved cardiac distensibility, characteristics of diastolic and also pump function in cardiac remodeling.

  4. Social media in vascular surgery.

    Science.gov (United States)

    Indes, Jeffrey E; Gates, Lindsay; Mitchell, Erica L; Muhs, Bart E

    2013-04-01

    There has been a tremendous growth in the use of social media to expand the visibility of various specialties in medicine. The purpose of this paper is to describe the latest updates on some current applications of social media in the practice of vascular surgery as well as existing limitations of use. This investigation demonstrates that the use of social networking sites appears to have a positive impact on vascular practice, as is evident through the incorporation of this technology at the Cleveland Clinic and by the Society for Vascular Surgery into their approach to patient care and physician communication. Overall, integration of social networking technology has current and future potential to be used to promote goals, patient awareness, recruitment for clinical trials, and professionalism within the specialty of vascular surgery. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  5. Underwater colorectal EMR: remodeling endoscopic mucosal resection.

    Science.gov (United States)

    Curcio, Gabriele; Granata, Antonino; Ligresti, Dario; Tarantino, Ilaria; Barresi, Luca; Liotta, Rosa; Traina, Mario

    2015-05-01

    Underwater EMR (UEMR) has been reported as a new technique for the removal of large sessile colorectal polyps without need for submucosal injection. To evaluate (1) outcomes of UEMR, (2) whether UEMR can be easily performed by an endoscopist skilled in traditional EMR without specific dedicated training in UEMR, and (3) whether EUS is required before UEMR. Prospective, observational study. Single, tertiary-care referral center. Underwater EMR. Complete resection and adverse events. A total of 72 consecutive patients underwent UEMR of 81 sessile colorectal polyps. EUS was performed before UEMR in 9 cases (11.1%) with a suspicious mucosal/vascular pattern. The mean polyp size was 18.7 mm (range 10-50 mm); the mean UEMR time was 11.8 minutes. Fifty-five polyps (68%) were removed en bloc, and 26 (32%) were removed with a piecemeal technique. Histopathology consisted of tubular adenomas (25.9%), tubulovillous adenomas (5%), adenomas with high-grade dysplasia (42%), serrated polyps (4.9%), carcinoma in situ (13.6%), and hyperplastic polyps (8.6%). Surveillance colonoscopy was scheduled at 3 months. Complete resection was successful in all patients. No adverse events or recurrence was recorded in any of the patients. Limited follow-up; single-center, uncontrolled study. Interventional endoscopists skilled in conventional EMR performed UEMR without specific dedicated training. EUS may not be required for lesions with no invasive features on high-definition narrow-band imaging. UEMR appears to be an effective and safe alternative to traditional EMR and could eventually improve the way in which we can effectively and safely treat colorectal lesions. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

  6. Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Keith Dadson

    Full Text Available Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM remodeling in response to pressure overload (PO. Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO and wild-type (WT mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson's trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects.

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

    Science.gov (United States)

    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.

  8. Long-term vascular contractility assay using genipin-modified muscular thin films

    International Nuclear Information System (INIS)

    Hald, Eric S; Steucke, Kerianne E; Reeves, Jack A; Win, Zaw; Alford, Patrick W

    2014-01-01

    Vascular disease is a leading cause of death globally and typically manifests chronically due to long-term maladaptive arterial growth and remodeling. To date, there is no in vitro technique for studying vascular function over relevant disease time courses that both mimics in vivo-like tissue structure and provides a simple readout of tissue stress. We aimed to extend tissue viability in our muscular thin film contractility assay by modifying the polydimethylsiloxane (PDMS) substrate with micropatterned genipin, allowing extracellular matrix turnover without cell loss. To achieve this, we developed a microfluidic delivery system to pattern genipin and extracellular matrix proteins on PDMS prior to cell seeding. Tissues constructed using this method showed improved viability and maintenance of in vivo-like lamellar structure. Functional contractility of tissues fabricated on genipin-modified substrates remained consistent throughout two weeks in culture. These results suggest that muscular thin films with genipin-modified PDMS substrates are a viable method for conducting functional studies of arterial growth and remodeling in vascular diseases. (paper)

  9. Development of an electrospun biomimetic polyurea scaffold suitable for vascular grafting.

    Science.gov (United States)

    Madhavan, Krishna; Frid, Maria G; Hunter, Kendall; Shandas, Robin; Stenmark, Kurt R; Park, Daewon

    2018-01-01

    The optimization of biomechanical and biochemical properties of a vascular graft to render properties relevant to physiological environments is a major challenge today. These critical properties of a vascular graft not only regulate its stability and integrity, but also control invasion of cells for scaffold remodeling permitting its integration with native tissue. In this work, we have synthesized a biomimetic scaffold by electrospinning a blend of a polyurea, poly(serinol hexamethylene urea) (PSHU), and, a polyester, poly-ε-caprolactone (PCL). Mechanical properties of the scaffold were varied by varying polymer blending ratio and electrospinning flow rate. Mechanical characterization revealed that scaffolds with lower PSHU content relative to PCL content resulted in elasticity close to native mammalian arteries. We also found that increasing electrospinning flow rates also increased the elasticity of the matrix. Optimization of elasticity generated scaffolds that enabled vascular smooth muscle cells (SMCs) to adhere, grow and maintain a SMC phenotype. The 30/70 scaffold also underwent slower degradation than scaffolds with higher PSHU content, thereby, providing the best option for in vivo remodeling. Further, Gly-Arg-Gly-Asp-Ser (RGD) covalently conjugated to the polyurea backbone in 30/70 scaffold resulted in significantly increased clotting times. Reducing surface thrombogenicity by the conjugation of RGD is critical to avoiding intimal hyperplasia. Hence, biomechanical and biochemical properties of a vascular graft can be balanced by optimizing synthesis parameters and constituent components. For these reasons, the optimized RGD-conjugated 30/70 scaffold electrospun at 2.5 or 5 mL/h has great potential as a suitable material for vascular grafting applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 278-290, 2018. © 2017 Wiley Periodicals, Inc.

  10. 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.

  11. 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.

  12. [The future of vascular medicine].

    Science.gov (United States)

    Kroeger, K; Luther, B

    2014-10-01

    In the future vascular medicine will still have a great impact on health of people. It should be noted that the aging of the population does not lead to a dramatic increase in patient numbers, but will be associated with a changing spectrum of co-morbidities. In addition, vascular medical research has to include the intensive care special features of vascular patients, the involvement of vascular medicine in a holistic concept of fast-track surgery, a geriatric-oriented intensive monitoring and early geriatric rehabilitation. For the future acceptance of vascular medicine as a separate subject area under delimitation of cardiology and radiology is important. On the other hand, the subject is so complex and will become more complex in future specialisations that mixing of surgery and angiology is desirable, with the aim to preserve the vascular surgical knowledge and skills on par with the medical and interventional measures and further develop them. Only large, interdisciplinary guided vascular centres will be able to provide timely diagnosis and therapy, to deal with the growing multi-morbidity of the patient, to perform complex therapies even in an acute emergency and due to sufficient number of cases to present with well-trained and experienced teams. These requirements are mandatory to decrease patients' mortality step by step. Georg Thieme Verlag KG Stuttgart · New York.

  13. 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.

  14. Equibiaxial cyclic stretch stimulates fibroblasts to rapidly remodel fibrin.

    Science.gov (United States)

    Balestrini, Jenna Leigh; Billiar, Kristen Lawrence

    2006-01-01

    Understanding the effects of the mechanical environment on wound healing is critical for developing more effective treatments to reduce scar formation and contracture. The aim of this study was to investigate the effects of dynamic mechanical stretch on cell-mediated early wound remodeling independent of matrix alignment which obscures more subtle remodeling mechanisms. Cyclic equibiaxial stretch (16% stretch at 0.2 Hz) was applied to fibroblast-populated fibrin gel in vitro wound models for eight days. Compaction, density, tensile strength, and collagen content were quantified as functional measures of remodeling. Stretched samples were approximately ten times stronger, eight-fold more dense, and eight times thinner than statically cultured samples. These changes were accompanied by a 15% increase in net collagen but no significant differences in cell number or viability. When collagen crosslinking was inhibited in stretched samples, the extensibility increased and the strength decreased. The apparent weakening was due to a reduction in compaction rather than a decrease in ability of the tissue to withstand tensile forces. Interestingly, inhibiting collagen crosslinking had no measurable effects on the statically cultured samples. These results indicate that amplified cell-mediated compaction and even a slight addition in collagen content play substantial roles in mechanically induced wound strengthening. These findings increase our understanding of how mechanical forces guide the healing response in skin, and the methods employed in this study may also prove valuable tools for investigating stretch-induced remodeling of other planar connective tissues and for creating mechanically robust engineered tissues.

  15. Animal experiment of periodontal tissue remodeling in application of ...

    African Journals Online (AJOL)

    The aim of the present study is to observe the remodeling of periodontal tissue in application of miniimplant anchorage for incisor intrusion in dogs. Six adult male beagle dogs were used for the experiment. On the buccal site, a mini-implant was placed at the interalveolar septum between the maxillary second incisor and ...

  16. Energy Efficiency Measures to Incorporate into Remodeling Projects

    Energy Technology Data Exchange (ETDEWEB)

    Liaukus, C. [Building America Research Alliance, Kent, WA (United States)

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of U.S. households compared to piecemeal remodeling efforts. In this report, the U.S Department of Energy Building America Retrofit Alliance research team examines the improvement of a home’s energy performance in an opportunistic way by examining what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for energy efficiency upgrades to occur at the same time as remodeling proejcts. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home’s energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  17. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula, E-mail: paulasa@fmb.unesp.br [Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, São Paulo, SP (Brazil)

    2016-05-15

    Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis.

  18. CREB Selectively Controls Learning-Induced Structural Remodeling of Neurons

    Science.gov (United States)

    Middei, Silvia; Spalloni, Alida; Longone, Patrizia; Pittenger, Christopher; O'Mara, Shane M.; Marie, Helene; Ammassari-Teule, Martine

    2012-01-01

    The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons…

  19. Modeling collagen remodeling in tissue engineered cardiovascular tissues

    NARCIS (Netherlands)

    Soares, A.L.F.

    2012-01-01

    Commonly, heart valve replacements consist of non-living materials lacking the ability to grow, repair and remodel. Tissue engineering (TE) offers a promising alternative to these replacement strategies since it can overcome its disadvantages. The technique aims to create an autologous living tissue

  20. Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    Tjin, Gavin; White, Eric S; Faiz, Alen; Sicard, Delphine; Tschumperlin, Daniel J; Mahar, Annabelle; Kable, Eleanor P W; Burgess, Janette K

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with feweffective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linkingmediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease

  1. Atrioventricular node functional remodeling induced by atrial fibrillation.

    Science.gov (United States)

    Zhang, Youhua; Mazgalev, Todor N

    2012-09-01

    The atrioventricular node (AVN) plays a vital role in determining the ventricular rate during atrial fibrillation (AF). AF results in profound electrophysiological and structural remodeling in the atria as well as the sinus node. However, it is unknown whether AVN undergoes remodeling during AF. To determine whether AVN undergoes functional remodeling during AF. AVN conduction properties were studied in vitro in 9 rabbits with AF and 10 normal controls. A previously validated index of AVN dual-pathway electrophysiology, His-electrogram alternans, was used to monitor fast-pathway or slow-pathway (SP) AVN conduction in these experiments. AVN conduction properties were further studied in vivo in 7 dogs with chronic AF and 8 controls. Compared with the control rabbits, the rabbits with AF had a longer AVN conduction time (83 ± 16 ms vs 68 ± 7 ms; P AVN effective refractory period (141 ± 27 ms vs 100 ± 9 ms; P AVN effective refractory period and a slower ventricular rate during AF compared with the controls. Pronounced AVN functional electrophysiological remodeling occurs after long-term AF, which could lead to a spontaneous slowing of the ventricular rate. Furthermore, the SP dominance during AF underscores the effectiveness of its modification by ablation for ventricular rate control during AF. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  2. Modeling and remodeling of the collagen architecture in cardiovascular tissues

    NARCIS (Netherlands)

    Driessen, N.J.B.

    2006-01-01

    Heart valve replacement by a mechanical or biological prosthesis represents a common surgical therapy for end-stage valvular heart diseases. A critical drawback of these prostheses is the inability to grow, repair and remodel in response to changes in the tissue’s environment. Tissue engineering

  3. Age-related motor unit remodeling in the Tibialis Anterior.

    Science.gov (United States)

    Siddiqi, Ariba; Kumar, Dinesh; Arjunan, Sridhar

    2015-01-01

    Limited studies exist on the use of surface electromyogram (EMG) signal features to detect age-related motor unit remodeling in the Tibialis Anterior. Motor unit remodeling leads to declined muscle strength and force steadiness during submaximal contractions which are factors for risk of falls in the elderly. This study investigated the remodeling phenomena in the Tibialis Anterior using sample entropy and higher order statistics. Eighteen young (26.1 ± 2.9 years) and twelve elderly (68.7 ± 9.0 years) participants performed isometric dorsiflexion of the ankle at 20% maximal voluntary contraction (MVC) and their Tibialis Anterior (TA) EMG was recorded. Sample entropy, Gaussianity and Linearity Test statistics were calculated from the recorded EMG for each MVC. Shapiro-Wilk test was used to determine normality, and either a two-tail student t-test or Wilcoxon rank sum test was performed to determine significant difference in the EMG features between the young and old cohorts. Results show age-related motor unit remodeling to be depicted by decreased sample entropy (p <; 0.1), increased non-Gaussianity (p <; 0.05) and lesser degree of linearity in the elderly. This is due to the increased sparsity of the MUAPs as a result of the denervation-reinnervation process, and the decrease in total number of motor units.

  4. Lung tissue remodeling in the acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Souza Alba Barros de

    2003-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro­liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patient?s prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.

  5. Fronto-Orbital Advancement and Total Calvarial Remodelling for Craniosynostosis

    International Nuclear Information System (INIS)

    Haq, E. U.; Aman, S.; Tammimy, M. S.; Ahmad, R. S.

    2014-01-01

    Objective: To describe the results of fronto-orbital advancement and remodelling for craniosynostosis in children. Study Design: Case series. Place and Duration of Study: Department of Plastic Surgery, Combined Military Hospital, Rawalpindi, from June 2009 to June 2012. Methodology: All the patients with cranial suture synostosis operated were included in the study. Those patients who were lost to follow-up were excluded. Variables considered were age, gender, type of synostosis, intracranial pressure, and history of previous surgeries for the same problem. Outcome measures were studied in terms of improvement of skull measurements (anteroposterior and bicoronal), duration of surgery, hospital stay, blood transfusions, complications and parents satisfaction. Results: A total of 36 patients were included in the study. Male to female ratio was 3:1. The age ranged from 5 to 54 months. Thirty two patients presented with non-syndromic and four with syndromic craniosynostosis. Fronto orbital advancement and total calvarial remodelling was done in 26 and 10 patients respectively. There was improvement in the skull measurements and the parents were satisfied in all cases with the skull shape. Complications occurred in 11.1% including chest and wound infection and one death. Conclusion: Fronto-orbital advancement and remodelling is an effective procedure for the correction of craniosynostosis, however, individual cases may require other procedures like total calvarial remodelling. (author)

  6. Vascular and valvular calcifications in chronic hemodialysis patients

    Directory of Open Access Journals (Sweden)

    María Elena Bruzzone

    2014-12-01

    Full Text Available Introduction: Vascular and valvular calcifications are a frequent complication in dialyzed patients and are connected to an increased morbi-mortality. Many radiological methods (TAC multiple slices and with electrons emission have been used to investigate the presence of vascular calcifications in this population, but only few works have been focused on simple radiology. Objectives: The objectives of this work are to evaluate vascular calcifications by means of Kauppila index in hemodialysis prevalent patients, identify linked risk factors and determine their association with heart valves calcification. Methods: 95 stable patients under hemodialysis were surveyed during a period of 6 months longer. Abdominal Rx simple profile were performed on all patients to evaluate calcification of abdominal aorta by Kauppila index and twodimensional echocardiogram to detect valvular calcifications. Data were collected about sex, age, diabetes, Hypertension, tabaquism, dislipemia and bone-mineral metabolism. Results: 64.5% of the patients showed vascular calcifications. Average Kauppila index was 6.25. Age and time on dialysis correlated with vascular calcifications. In 31.6 % of individuals valvular calcifications were found, which presented significant association with diabetes and Kauppila Index. Conclusions: Vascular and valvular calcifications were frequent in the surveyed population. Kauppila index correlated with age, time on dialysis and valvular calcifications. Heart valves calcification was associated with diabetes.

  7. Constructal vascularized structures

    Science.gov (United States)

    Cetkin, Erdal

    2015-06-01

    Smart features such as self-healing and selfcooling require bathing the entire volume with a coolant or/and healing agent. Bathing the entire volume is an example of point to area (or volume) flows. Point to area flows cover all the distributing and collecting kinds of flows, i.e. inhaling and exhaling, mining, river deltas, energy distribution, distribution of products on the landscape and so on. The flow resistances of a point to area flow can be decreased by changing the design with the guidance of the constructal law, which is the law of the design evolution in time. In this paper, how the flow resistances (heat, fluid and stress) can be decreased by using the constructal law is shown with examples. First, the validity of two assumptions is surveyed: using temperature independent Hess-Murray rule and using constant diameter ducts where the duct discharges fluid along its edge. Then, point to area types of flows are explained by illustrating the results of two examples: fluid networks and heating an area. Last, how the structures should be vascularized for cooling and mechanical strength is documented. This paper shows that flow resistances can be decreased by morphing the shape freely without any restrictions or generic algorithms.

  8. Penyekat Beta sebagai Terapi Anti-Remodeling pada Gagal Jantung

    Directory of Open Access Journals (Sweden)

    Hilman Zulkifli Amin

    2015-09-01

    Full Text Available Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 Penyakit kardiovaskular merupakan penyebab kematian utama dan setiap tahunnya terjadi 50 juta kematian di seluruh dunia. Gagal jantung tercatat sebagai salah satu penyakit kardiovaskularyang sering terjadi. Pada gagal jantung, terjadi remodelling sel yang mengakibatkan penurunanfungsi pompa jantung. Seiring dengan kemajuan penelitian di bidang kardiovaskuler, penyekatbeta telah diteliti penggunaannya sebagai terapi anti-remodelling. Sampai sekarang, penelitian danstudi terkait hal tersebut masih terus dilakukan. Tujuan penulisan makalah ini untuk menjelaskanperan penyekat beta sebagai terapi anti-remodelling pada gagal jantung. Pencarian terstrukturmelalui PubMed mendapatkan 93 artikel, setelah disesuaikan dengan kriteria eksklusi dan inklusididapatkan 25 artikel. Setelah membaca artikel secara lengkap, didapatkan 11 artikel yang sesuai.Kemudian artikel tersebut ditelaah dalam menentukan validitas, relevansi, dan aplikabilitas. Dari 11artikel yang ditelaah kritis, didapatkan bahwa beta-blocker dapat berperan sebagai anti-remodellingmelalui peningkatan fungsi jantung sebagaimana terlihat pada kenaikan ejection fraction (EF,penurunan left ventricular end systolic volume (LVESV dan left ventricular end diastolic volume(LVEDV pada pasien gagal jantung. Kata Kunci: penyekat beta, anti-remodelling, gagal jantung Beta-Blocker as Anti-Remodeling Therapy in Heart Failure Abstract Cardiovascular diseases still become the leading cause of death in the world. All over the world, there are approximately 50 million deaths every year caused by cardiovascular diseases.Heart failure is known as one of cardiovascular diseases that frequently happened. In heart failurestate, there is a cell remodeling condition that implicated to lowering heart pump function. As thedevelopment progress of cardiovascular researches, beta-blocker has also been studied for its useas anti-remodeling therapy. Up to

  9. Hierarchical recruitment of ribosomal proteins and assembly factors remodels nucleolar pre-60S ribosomes.

    Science.gov (United States)

    Biedka, Stephanie; Micic, Jelena; Wilson, Daniel; Brown, Hailey; Diorio-Toth, Luke; Woolford, John L

    2018-04-24

    Ribosome biogenesis involves numerous preribosomal RNA (pre-rRNA) processing events to remove internal and external transcribed spacer sequences, ultimately yielding three mature rRNAs. Removal of the internal transcribed spacer 2 spacer RNA is the final step in large subunit pre-rRNA processing and begins with endonucleolytic cleavage at the C 2 site of 27SB pre-rRNA. C 2 cleavage requires the hierarchical recruitment of 11 ribosomal proteins and 14 ribosome assembly factors. However, the function of these proteins in C 2 cleavage remained unclear. In this study, we have performed a detailed analysis of the effects of depleting proteins required for C 2 cleavage and interpreted these results using cryo-electron microscopy structures of assembling 60S subunits. This work revealed that these proteins are required for remodeling of several neighborhoods, including two major functional centers of the 60S subunit, suggesting that these remodeling events form a checkpoint leading to C 2 cleavage. Interestingly, when C 2 cleavage is directly blocked by depleting or inactivating the C 2 endonuclease, assembly progresses through all other subsequent steps. © 2018 Biedka et al.

  10. Myocardial remodeling and bioelectric changes in tachycardia-induced heart failure in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Song, B.; Wang, B.N.; Chen, D.N.; Luo, Z.G. [Department of Cardiovascular Medicine, The First Affiliated Hospital, Anhui Medical University, HeFei, Anhui Province (China)

    2013-09-06

    In this study, electrical and structural remodeling of ventricles was examined in tachycardia-induced heart failure (HF). We studied two groups of weight-matched adult male mongrel dogs: a sham-operated control group (n=5) and a pacing group (n=5) that underwent ventricular pacing at 230 bpm for 3 weeks. Clinical symptoms of congestive HF were observed in both groups. Their hemodynamic parameters were determined and the severity of the HF was evaluated by M-mode echocardiography. Changes in heart morphology were observed by scanning electron and light microscopy. Ventricular action potential duration (APD), as well as the 50 and 90% APD were measured in both groups. All dogs exhibited clinical symptoms of congestive HF after rapid right ventricular pacing for 3 weeks. These data indicate that rapid, right ventricular pacing produces a useful experimental model of low-output HF in dogs, characterized by biventricular pump dysfunction, biventricular cardiac dilation, and non-ischemic impairment of left ventricular contractility. Electrical and structural myocardial remodeling play an essential role in congestive HF progression, and should thus be prevented.

  11. Functional delineation of three groups of the ATP-dependent family of chromatin remodeling enzymes.

    NARCIS (Netherlands)

    Boyer, L.A.; Logie, C.; Bonte, E; Becker, P.B.; Wade, P.A.; Wolff, A.P.; Wu, C.; Imbalzano, A.N.; Peterson, C.L.

    2000-01-01

    ATP-dependent chromatin remodeling enzymes antagonize the inhibitory effects of chromatin. We compare six different remodeling complexes: ySWI/SNF, yRSC, hSWI/SNF, xMi-2, dCHRAC, and dNURF. We find that each complex uses similar amounts of ATP to remodel nucleosomal arrays at nearly identical rates.

  12. Premature loss of bone remodeling compartment canopies is associated with deficient bone formation

    DEFF Research Database (Denmark)

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Søe, Kent

    2011-01-01

    A remarkable property of bone remodeling is that osteoblasts form bone matrix exactly where and when osteoclasts have removed it. The bone remodeling compartment (BRC) canopies that cover bone surfaces undergoing remodeling, were proposed to be critical players in this mechanism. Here, we provide...

  13. Magnitude and duration of stretch modulate fibroblast remodeling.

    Science.gov (United States)

    Balestrini, Jenna L; Billiar, Kristen L

    2009-05-01

    Mechanical cues modulate fibroblast tractional forces and remodeling of extracellular matrix in healthy tissue, healing wounds, and engineered matrices. The goal of the present study is to establish dose-response relationships between stretch parameters (magnitude and duration per day) and matrix remodeling metrics (compaction, strength, extensibility, collagen content, contraction, and cellularity). Cyclic equibiaxial stretch of 2-16% was applied to fibroblast-populated fibrin gels for either 6 h or 24 h/day for 8 days. Trends in matrix remodeling metrics as a function of stretch magnitude and duration were analyzed using regression analysis. The compaction and ultimate tensile strength of the tissues increased in a dose-dependent manner with increasing stretch magnitude, yet remained unaffected by the duration in which they were cycled (6 h/day versus 24 h/day). Collagen density increased exponentially as a function of both the magnitude and duration of stretch, with samples stretched for the reduced duration per day having the highest levels of collagen accumulation. Cell number and failure tension were also dependent on both the magnitude and duration of stretch, although stretch-induced increases in these metrics were only present in the samples loaded for 6 h/day. Our results indicate that both the magnitude and the duration per day of stretch are critical parameters in modulating fibroblast remodeling of the extracellular matrix, and that these two factors regulate different aspects of this remodeling. These findings move us one step closer to fully characterizing culture conditions for tissue equivalents, developing improved wound healing treatments and understanding tissue responses to changes in mechanical environments during growth, repair, and disease states.

  14. Evidence for a role of macrophage migration inhibitory factor in vascular disease.

    Science.gov (United States)

    Chen, Zhiping; Sakuma, Masashi; Zago, Alexandre C; Zhang, Xiaobin; Shi, Can; Leng, Lin; Mizue, Yuka; Bucala, Richard; Simon, Daniel

    2004-04-01

    Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice. Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or "positive remodeling" that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury. Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.

  15. VESsel GENeration Analysis (VESGEN): Innovative Vascular Mappings for Astronaut Exploration Health Risks and Human Terrestrial Medicine

    Science.gov (United States)

    Parsons-Wingerter, Patricia; Kao, David; Valizadegan, Hamed; Martin, Rodney; Murray, Matthew C.; Ramesh, Sneha; Sekaran, Srinivaas

    2017-01-01

    Currently, astronauts face significant health risks in future long-duration exploration missions such as colonizing the Moon and traveling to Mars. Numerous risks include greatly increased radiation exposures beyond the low earth orbit (LEO) of the ISS, and visual and ocular impairments in response to microgravity environments. The cardiovascular system is a key mediator in human physiological responses to radiation and microgravity. Moreover, blood vessels are necessarily involved in the progression and treatment of vascular-dependent terrestrial diseases such as cancer, coronary vessel disease, wound-healing, reproductive disorders, and diabetes. NASA developed an innovative, globally requested beta-level software, VESsel GENeration Analysis (VESGEN) to map and quantify vascular remodeling for application to astronaut and terrestrial health challenges. VESGEN mappings of branching vascular trees and networks are based on a weighted multi-parametric analysis derived from vascular physiological branching rules. Complex vascular branching patterns are determined by biological signaling mechanisms together with the fluid mechanics of multi-phase laminar blood flow.

  16. Supplementing exposure to hypoxia with a copper depleted diet does not exacerbate right ventricular remodeling in mice.

    Directory of Open Access Journals (Sweden)

    Ella M Poels

    Full Text Available Pulmonary hypertension and subsequent right ventricular (RV failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure.Six week old mice were subjected to normoxia (N; 21% O2 or hypoxia (H; 10% O2 during a period of 8 weeks and received either a normal diet (Cu+ or a copper depleted diet (Cu-. Cardiac function was assessed by echocardiography and MRI analysis.Here, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10% is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.

  17. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio.

    Science.gov (United States)

    Wang, Yurong; Wang, Bin; Guerram, Mounia; Sun, Li; Shi, Wei; Tian, Chongchong; Zhu, Xiong; Jiang, Zhenzhou; Zhang, Luyong

    2015-10-06

    Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.

  18. Mutation of Neuron-Specific Chromatin Remodeling Subunit BAF53b: Rescue of Plasticity and Memory by Manipulating Actin Remodeling

    Science.gov (United States)

    Ciernia, Annie Vogel; Kramár, Enikö A.; Matheos, Dina P.; Havekes, Robbert; Hemstedt, Thekla J.; Magnan, Christophe N.; Sakata, Keith; Tran, Ashley; Azzawi, Soraya; Lopez, Alberto; Dang, Richard; Wang, Weisheng; Trieu, Brian; Tong, Joyce; Barrett, Ruth M.; Post, Rebecca J.; Baldi, Pierre; Abel, Ted; Lynch, Gary; Wood, Marcelo A.

    2017-01-01

    Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic…

  19. Prefabrication of axial vascularized tissue engineering coral bone by an arteriovenous loop: A better model

    International Nuclear Information System (INIS)

    Dong Qingshan; Shang Hongtao; Wu Wei; Chen Fulin; Zhang Junrui; Guo Jiaping; Mao Tianqiu

    2012-01-01

    The most important problem for the survival of thick 3-dimensional tissues is the lack of vascularization in the context of bone tissue engineering. In this study, a modified arteriovenous loop (AVL) was developed to prefabricate an axial vascularized tissue engineering coral bone in rabbit, with comparison of the arteriovenous bundle (AVB) model. An arteriovenous fistula between rabbit femoral artery and vein was anastomosed to form an AVL. It was placed in a circular side groove of the coral block. The complex was wrapped with an expanded-polytetrafluoroethylene membrane and implanted beneath inguinal skin. After 2, 4, 6 and 8 weeks, the degree of vascularization was evaluated by India ink perfusion, histological examination, vascular casts, and scanning electron microscopy images of vascular endangium. Newly formed fibrous tissues and vasculature extended over the surfaces and invaded the interspaces of entire coral block. The new blood vessels robustly sprouted from the AVL. Those invaginated cavities in the vascular endangium from scanning electron microscopy indicated vessel's sprouted pores. Above indexes in AVL model are all superior to that in AVB model, indicating that the modified AVL model could more effectively develop vascularization in larger tissue engineering bone. - Highlights: ► A modified arteriovenous loop (AVL) model in rabbit was developed in this study. ► Axial prevascularization was induced in a larger coral block by using the AVL. ► The prefabrication of axial vascularized coral bone is superior as vascular carrier.

  20. Oscillation of Angiogenesis with Vascular Dropout in Diabetic Retinopathy by VESsel GENeration Analysis (VESGEN)

    Science.gov (United States)

    Parsons-Wingerter, Patricia; Radbakrishnan, Krisbnan; Vickerman, Mary B.; Kaiser, Peter K.

    2010-01-01

    PURPOSE. Vascular dropout and angiogenesis are hallmarks of the progression of diabetic retinopathy (DR). However, current evaluation of DR relies on grading of secondary vascular effects, such as microaneurysms and hemorrhages, by clinical examination instead of by evaluation of actual vascular changes. The purpose of this study was to map and quantify vascular changes during progression of DR by VESsel GENeration Analysis (VESGEN). METHODS. In this prospective cross-sectional study, 15 eyes with DR were evaluated with fluorescein angiography (FA) and color fundus photography, and were graded using modified Early Treatment Diabetic Retinopathy Study criteria. FA images were separated by semiautomatic image processing into arterial and venous trees. Vessel length density (L(sub v)), number density (N(sub v)), and diameter (D(sub v)) were analyzed in a masked fashion with VESGEN software. Each vascular tree was automatically segmented into branching generations (G(sub 1)...G(sub 8) or G(sub 9)) by vessel diameter and branching. Vascular remodeling status (VRS) for N(sub v) and L(sub v) was graded 1 to 4 for increasing severity of vascular change. RESULTS. By N(sub v) and L(sub v), VRS correlated significantly with the independent clinical diagnosis of mild to proliferative DR (13/15 eyes). N(sub v) and L(sub v) of smaller vessels (G(sub >=6) increased from VRS1 to VRS2 by 2.4 X and 1.6 X, decreased from VRS2 to VRS3 by 0.4 X and 0.6X, and increased from VRS3 to VRS4 by 1.7 X and 1.5 X (P < 0.01). Throughout DR progression, the density of larger vessels (G(sub 1-5)) remained essentially unchanged, and D(sub v1-5) increased slightly. CONCLUSIONS. Vessel density oscillated with the progression of DR. Alternating phases of angiogenesis/neovascularization and vascular dropout were dominated first by remodeling of arteries and subsequently by veins.

  1. Diabetes and Retinal Vascular Dysfunction

    Directory of Open Access Journals (Sweden)

    Eui Seok Shin

    2014-01-01

    Full Text Available Diabetes predominantly affects the microvascular circulation of the retina resulting in a range of structural changes unique to this tissue. These changes ultimately lead to altered permeability, hyperproliferation of endothelial cells and edema, and abnormal vascularization of the retina with resulting loss of vision. Enhanced production of inflammatory mediators and oxidative stress are primary insults with significant contribution to the pathogenesis of diabetic retinopathy (DR. We have determined the identity of the retinal vascular cells affected by hyperglycemia, and have delineated the cell autonomous impact of high glucose on function of these cells. We discuss some of the high glucose specific changes in retinal vascular cells and their contribution to retinal vascular dysfunction. This knowledge provides novel insight into the molecular and cellular defects contributing to the development and progression of diabetic retinopathy, and will aid in the development of innovative, as well as target specific therapeutic approaches for prevention and treatment of DR.

  2. Vascular graft infections with Mycoplasma

    DEFF Research Database (Denmark)

    Levi-Mazloum, Niels Donald; Skov Jensen, J; Prag, J

    1995-01-01

    laboratory techniques, the percentage of culture-negative yet grossly infected vascular grafts seems to be increasing and is not adequately explained by the prior use of antibiotics. We have recently reported the first case of aortic graft infection with Mycoplasma. We therefore suggest the hypothesis...... that the large number of culture-negative yet grossly infected vascular grafts may be due to Mycoplasma infection not detected with conventional laboratory technique....

  3. 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....

  4. Facial vascular malformations in children

    International Nuclear Information System (INIS)

    Brunelle, F.O.; Lallemand, D.; Chaumont, P.; Teillac, D.; Manach, Y.

    1988-01-01

    The authors present their experience with conventional and digital angiography of vascular malformations of the head and neck in children. 22 hemangioendotheliomas, 8 venous angiomas, and 3 arteriovenous fistula were studied. 22 patients were embolised. DSA offers many advantages during the diagnostic as well as during the therapeutic phase of angiography. Embolization appears to have a major role in treatment of such vascular malformations. (orig.)

  5. Vascular anatomy of the pig kidney glomerulus: a qualitative study of corrosion casts.

    Science.gov (United States)

    Moore, B J; Holmes, K R; Xu, L X

    1992-09-01

    Pig kidney glomerular vascular anatomy was studied by scanning electron microscopy of vascular corrosion casts. A generalized vascular architecture is presented to describe the pig kidney glomerulus based upon the observation of 3,800 vascular cast glomeruli. The relative simplicity of the pig glomerular vascular architecture has allowed the characterization of different vascular segments more completely than has been possible in other mammals. Based upon relationships to the afferent arteriole, a nomenclature and definition of primary, secondary, tertiary and anastomotic vessels is proposed for the distributing vessels comprising the glomerular tuft. The existence and formation of a large central hemispheric vessel deep within the confines of a glomerular hemisphere is micrographically documented. Micrographic evidence is presented supporting the formation of the single efferent arteriole by the merging of two central hemispheric vessels within the confines of the glomerular tuft. Failure of the merging of these two vessels may result in multiple efferent arterioles.

  6. Angiogenesis, Cancer, and Vascular Aging

    Directory of Open Access Journals (Sweden)

    Junji Moriya

    2017-10-01

    Full Text Available Several lines of evidence have revealed that the angiogenic response to ischemic injury declines with age, which might account for the increased morbidity and mortality of cardiovascular disease (CVD among the elderly. While impairment of angiogenesis with aging leads to delayed wound healing or exacerbation of atherosclerotic ischemic diseases, it also inhibits the progression of cancer. Age-related changes of angiogenesis have been considered to at least partly result from vascular aging or endothelial cell senescence. There is considerable evidence supporting the hypothesis that vascular cell senescence contributes to the pathogenesis of age-related CVD, suggesting that vascular aging could be an important therapeutic target. Since therapeutic angiogenesis is now regarded as a promising concept for patients with ischemic CVD, it has become even more important to understand the detailed molecular mechanisms underlying impairment of angiogenesis in older patients. To improve the usefulness of therapeutic angiogenesis, approaches are needed that can compensate for impaired angiogenic capacity in the elderly while not promoting the development or progression of malignancy. In this review, we briefly outline the mechanisms of angiogenesis and vascular aging, followed by a description of how vascular aging leads to impairment of angiogenesis. We also examine potential therapeutic approaches that could enhance angiogenesis and/or vascular function in the elderly, as well as discussing the possibility of anti-senescence therapy or reversal of endothelial cell senescence.

  7. Predicted shortage of vascular surgeons in the United Kingdom: A matter for debate?

    Science.gov (United States)

    Harkin, D W; Beard, J D; Shearman, C P; Wyatt, M G

    2016-10-01

    Vascular surgery became a new independent surgical specialty in the United Kingdom (UK) in 2013. In this matter for debate we discuss the question, is there a "shortage of vascular surgeons in the United Kingdom?" We used data derived from the "Vascular Surgery United Kingdom Workforce Survey 2014", NHS Employers Electronic Staff Records (ESR), and the National Vascular Registry (NVR) surgeon-level public report to estimate current and predict future workforce requirements. We estimate there are approximately 458 Consultant Vascular Surgeons for the current UK population of 63 million, or 1 per 137,000 population. In several UK Regions there are a large number of relatively small teams (3 or less) of vascular surgeons working in separate NHS Trusts in close geographical proximity. In developed countries, both the number and complexity of vascular surgery procedures (open and endovascular) per capita population is increasing, and concerns have been raised that demand cannot be met without a significant expansion in numbers of vascular surgeons. Additional workforce demand arises from the impact of population growth and changes in surgical work-patterns with respect to gender, working-life-balance and 7-day services. We predict a future shortage of Consultant Vascular Surgeons in the UK and recommend an increase in training numbers and an expansion in the UK Consultant Vascular Surgeon workforce to accommodate population growth, facilitate changes in work-patterns and to create safe sustainable services. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  8. Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice.

    Science.gov (United States)

    Kyriakides, T R; Zhu, Y H; Yang, Z; Huynh, G; Bornstein, P

    2001-10-01

    The matricellular angiogenesis inhibitor, thrombospondin (TSP) 2, has been shown to be an important modulator of wound healing and the foreign body response. Specifically, TSP2-null mice display improved healing with minimal scarring and form well-vascularized foreign body capsules. In this study we performed subcutaneous implantation of sponges and investigated the resulting angiogenic and fibrogenic responses. Histological and immunohistochemical analysis of sponges, excised at 7, 14, and 21 days after implantation, revealed significant differences between TSP2-null and wild-type mice. Most notably, TSP2-null mice exhibited increased angiogenesis and fibrotic encapsulation of the sponge. However, invasion of dense tissue was compromised, even though its overall density was increased. Furthermore, histomorphometry and biochemical assays demonstrated a significant increase in the extracellular distribution of matrix metalloproteinase (MMP) 2, but no change in the levels of active transforming growth factor-beta(1). The alterations in neovascularization, dense tissue invasion, and MMP2 in TSP2-null mice coincided with the deposition of TSP2 in the extracellular matrix of wild-type animals. These observations support the proposed role of TSP2 as a modulator of angiogenesis and matrix remodeling during tissue repair. In addition, they provide in vivo evidence for a newly proposed function of TSP2 as a modulator of extracellular MMP2 levels.

  9. Cardiac remodeling following percutaneous mitral valve repair - initial results assessed by cardiovascular magnetic resonance imaging

    DEFF Research Database (Denmark)

    Radunski, U K; Franzen, O; Barmeyer, A

    2014-01-01

    PURPOSE: Percutaneous mitral valve repair with the MitraClip device (Abbott Vascular, Redwood City, California, USA) is a novel therapeutic option in patients with mitral regurgitation. This study evaluated the feasibility of cardiac volume measurements by cardiovascular magnetic resonance imaging...... (CMR) to assess reverse myocardial remodeling in patients after MitraClip implantation. MATERIALS AND METHODS: 12 patients underwent CMR at baseline (BL) before and at 6 months follow-up (FU) after MitraClip implantation. Cine-CMR was performed in short- and long-axes for the assessment of left...... end-systolic (48 [42 - 80] vs. 51 [40 - 81] ml/m(2); p = 0.48), and LA (87 [55 - 124] vs. 92 [48 - 137] ml/m(2); p = 0.20) volume indices between BL and FU. CONCLUSION: CMR enables the assessment of cardiac volumes in patients after MitraClip implantation. Our CMR findings indicate that percutaneous...

  10. Omega-3 Fatty Acids Modulate TRPV4 Function through Plasma Membrane Remodeling.

    Science.gov (United States)

    Caires, Rebeca; Sierra-Valdez, Francisco J; Millet, Jonathan R M; Herwig, Joshua D; Roan, Esra; Vásquez, Valeria; Cordero-Morales, Julio F

    2017-10-03

    Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is required for TRPV4 activity. Functional, lipid metabolome, and biophysical analyses demonstrated that ω-3 PUFAs enhance TRPV4 function in human endothelial cells and support the hypothesis that lipid metabolism and membrane remodeling regulate cell reactivity. We propose a model whereby the eicosanoid's epoxide group location increases membrane fluidity and influences the endothelial cell response by increasing TRPV4 channel activity. ω-3 PUFA-like molecules might be viable antihypertensive agents for targeting TRPV4 to reduce systemic blood pressure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. 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....

  12. Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Sarah E. Lutz

    2017-11-01

    Full Text Available Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs or caveolae to induce tissue inflammation. In the CNS, Th17 lymphocytes cross the blood-brain barrier (BBB before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE model for multiple sclerosis. We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.

  13. Spatio-Temporal Mapping of Matrix Remodeling and Evidence of in-situ Elastogenesis in Experimental Abdominal Aortic Aneurysms

    Science.gov (United States)

    Deb, Partha Pratim; Ramamurthi, Anand

    2014-01-01

    Spatio-temporal changes in the extracellular matrix (ECM) were studied within abdominal aortic aneurysms (AAA) generated in rats via elastase-infusion. At 7, 14, and 21 days post-induction, AAA tissues were divided into proximal, mid and distal regions based on their location relative to the renal arteries and region of maximal aortic diameter. Wall thicknesses differed significantly between the AAA spatial regions, initially increasing due to positive matrix remodeling, and then decreasing due to wall thinning and compaction of matrix as the disease progressed. Histological images analyzed using custom segmentation tools indicated significant differences in ECM composition and structure, versus healthy tissue and in the extent and nature of matrix remodeling, between the AAA spatial regions. Histology and immunofluorescence (IF) labeling provided evidence of neointimal AAA remodeling characterized by presence of elastin-containing fibers. This remodeling was effected by smooth muscle alpha actin-positive neointimal cells that transmission electron microscopy (TEM) showed to morphologically differ from medial SMCs. TEM of the neointima further showed presence of elongated deposits of amorphous elastin and presence of nascent, but not mature elastic fibers. These structures appeared to be deficient in at least one microfibrillar component, fibrillin-1, which is critical to mature elastic fiber assembly. The substantial production of elastin and elastic fiber-like structures that we observed in the AAA neointima, which was not observed elsewhere within AAA tissues, provides us a unique opportunity to capitalize on this auto-regenerative phenomenon and direct it from the standpoint of matrix organization towards restoring healthy aortic matrix structure, mechanics, and function. PMID:24799390

  14. Injuries to the vascular endothelium: vascular wall and endothelial dysfunction.

    Science.gov (United States)

    Fisher, Mark

    2008-01-01

    Vascular endothelial injury has multiple elements, and this article focuses on ischemia-related processes that have particular relevance to ischemic stroke. Distinctions between necrotic and apoptotic cell death provide a basic science context in which to better understand the significance of classical core and penumbra concepts of acute stroke, with apoptotic processes particularly prominent in the penumbra. The mitochondria are understood to serve as a reservoir of proteins that mediate apoptosis. Oxidative stress pathways generating reactive oxygen species (ROS) are prominent in endothelial injury, both ischemic and nonischemic, with prominent roles of enzyme- and nonenzymemediated pathways; mitochondria once again have a critical role, particularly in the nonenzymatic pathways generating ROS. Inflammation also contributes to vascular endothelial injury, and endothelial cells have the capacity to rapidly increase expression of inflammatory mediators following ischemic challenge; this leads to enhanced leukocyte-endothelial interactions mediated by selectins and adhesion molecules. Preconditioning consists of a minor version of an injurious event, which in turn may protect vascular endothelium from injury following a more substantial event. Presence of the blood-brain barrier creates unique responses to endothelial injury, with permeability changes due to impairment of endothelial-matrix interactions compounding altered vasomotor tone and tissue perfusion mediated by nitric oxide. Pharmacological protection against vascular endothelial injury can be provided by several of the phosphodiesterases (cilostazol and dipyridamole), along with statins. Optimal clinical responses for protection of brain vascular endothelium may use preconditioning as a model, and will likely require combined protection against apoptosis, ROS, and inflammation.

  15. Non-invasive vascular imaging: assessing tumour vascularity

    International Nuclear Information System (INIS)

    Delorme, S.; Knopp, M.V.

    1998-01-01

    Non-invasive assessment of vascularity is a new diagnostic approach to characterise tumours. Vascular assessment is based on the pathophysiology of tumour angiogenesis and its diagnostic implications for tumour biology, prognosis and therapy response. Two current techniques investigating vascular features in addition to morphology are Doppler ultrasonography and contrast-enhanced MRI. Diagnostic differentiation has been shown to be possible with Doppler, and a high degree of observed vascularity could be linked to an aggressive course of the disease. Dynamic MRI using gadolinium chelates is already used clinically to detect and differentiate tumours. The histological correlation shows that capillary permeability is increased in malignant tumours and is the best criterion for differentiation from benign processes. Permeability and perfusion factors seem to be more diagnostic than overall vessel density. New clinical applications are currently being established for therapy monitoring. Further instrumental developments will bring harmonic imaging in Doppler, and faster imaging techniques, higher spatial resolution and novel pharmacokinetic concepts in MRI. Upcoming contrast agents for both Doppler and MRI will further improve estimation of intratumoural blood volume and vascular permeability. (orig.)

  16. Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

    Science.gov (United States)

    Andrews, Rachel N.; Metheny-Barlow, Linda J.; Peiffer, Ann M.; Hanbury, David B.; Tooze, Janet A.; Bourland, J. Daniel; Hampson, Robert E.; Deadwyler, Samuel A.; Cline, J. Mark

    2017-01-01

    Andrews, R. N., Metheny-Barlow, L. J., Peiffer, A. M., Hanbury, D. B., Tooze, J. A., Bourland, J. D., Hampson, R. E., Deadwyler, S. A. and Cline, J. M. Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat. Res. 187, 599–611 (2017). Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6–11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and

  17. Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

    Science.gov (United States)

    Chen, Si; Knight, Walter E; Yan, Chen

    2018-04-23

    Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

  18. Compensatory Effect between Aortic Stiffening and Remodelling during Ageing.

    Directory of Open Access Journals (Sweden)

    Andrea Guala

    Full Text Available The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases.

  19. Compensatory Effect between Aortic Stiffening and Remodelling during Ageing.

    Science.gov (United States)

    Guala, Andrea; Camporeale, Carlo; Ridolfi, Luca

    2015-01-01

    The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases.

  20. Intradialytic Hypotension and Cardiac Remodeling: A Vicious Cycle

    Directory of Open Access Journals (Sweden)

    Chia-Ter Chao

    2015-01-01

    Full Text Available Hemodynamic instability during hemodialysis is a common but often underestimated issue in the nephrologist practice. Intradialytic hypotension, namely, a decrease of systolic or mean blood pressure to a certain level, prohibits the safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients. Studies have elucidated the potential mechanisms involved in the development of Intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance. Cardiac remodeling could also be one important piece of the puzzle. In this review, we intend to discuss the role of cardiac remodeling, including left ventricular hypertrophy, in the development of Intradialytic hypotension. In addition, we will also provide evidence that a bidirectional relationship might exist between Intradialytic hypotension and left ventricular hypertrophy in chronic dialysis patients. A more complete understanding of the complex interactions in between could assist the readers in formulating potential solutions for the reduction of both phenomena.

  1. p53 regulates cytoskeleton remodeling to suppress tumor progression.

    Science.gov (United States)

    Araki, Keigo; Ebata, Takahiro; Guo, Alvin Kunyao; Tobiume, Kei; Wolf, Steven John; Kawauchi, Keiko

    2015-11-01

    Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

  2. Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

    Science.gov (United States)

    Quinton, Lee J.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. PMID:25148693

  3. Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

    Science.gov (United States)

    Dong, Yan

    2016-05-01

    Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  4. Unexpected role of the copper transporter ATP7A in PDGF-induced vascular smooth

    Energy Technology Data Exchange (ETDEWEB)

    Ashino, T.; Varadarajan, S.; Urao, N.; Oshikawa, J.; Chen, G. -F.; Wang, H.; Huo, Y.; Finney, L.; Vogt, S.; McKinney, R. D.; Maryon, E. B.; Kaplan, J. H.; Ushio-Fukai, M.; Fukai, T. (Biosciences Division); ( XSD); ( PSC-USR); (Univ. of Illinois at Chicago); (Univ. of Minnesota)

    2010-09-09

    Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration. Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model. These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.

  5. Exposure to Experimental Preeclampsia in Mice Enhances the Vascular Response to Future Injury

    Science.gov (United States)

    Pruthi, Dafina; Khankin, Eliyahu V.; Blanton, Robert M.; Aronovitz, Mark; Burke, Suzanne D.; McCurley, Amy; Karumanchi, S. Ananth; Jaffe, Iris Z.

    2015-01-01

    Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One gender-specific risk factor is preeclampsia (PE), a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although PE resolves after delivery, exposed women are at increased long term risk of premature CVD and mortality. Preexisting CVD risk factors are associated with increased risk of developing PE but whether PE merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse PE model was used to test the hypothesis that PE causes an enhanced vascular response to future vessel injury. A PE-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein that induces hypertension and glomerular disease resembling human PE. Two months post-partum, sFlt-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in PE-exposed compared to control mice. Mice were then challenged with unilateral carotid injury. PE-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase, P<0.01) and vessel fibrosis (216% increase, P<0.001) compared to control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to PE. These data support a new model in which vessels exposed to PE retain a persistently enhanced vascular response to injury despite resolution of PE after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to PE. PMID:25712723

  6. The reversal phase of the bone-remodeling cycle

    DEFF Research Database (Denmark)

    Delaisse, Jean-Marie

    2014-01-01

    coincides with decreased osteoblast recruitment and impaired initiation of bone formation, that is, uncoupling. Overall, this review stresses that coupling does not only depend on molecules able to activate osteogenesis, but that it also demands the presence of osteoprogenitors and ordered cell......The reversal phase couples bone resorption to bone formation by generating an osteogenic environment at remodeling sites. The coupling mechanism remains poorly understood, despite the identification of a number of 'coupling' osteogenic molecules. A possible reason is the poor attention...

  7. Energy Efficiency Measures to Incorporate into Remodeling Projects

    Energy Technology Data Exchange (ETDEWEB)

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of the households in our nation compared to more piecemeal remodeling efforts. Even when programs like the Weatherization Assistance Program and Home Performance with ENERGY STAR are considered, homes that have had a comprehensive energy makeover still represent a small fraction of the 111.1 million households. In this report, the U.S Department of Energy Building America Retrofit Alliance research team looks at the improvement of a home's energy performance in an opportunistic way: it examines what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for the possibility for people who would not normally pursue energy efficiency but will remodel their kitchen or re-side their home to improve their home's performance at the same time. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home's energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  8. "Tipping" extracellular matrix remodeling towards regression of liver fibrosis

    DEFF Research Database (Denmark)

    Magdaleno, Fernando; Schierwagen, Robert; Uschner, Frank E

    2018-01-01

    Fibrosis development was initially conceived as an incessant progressive condition. Nowadays, it has become evident that fibrotic tissue undergoes a continuous two-way process: fibrogenesis and fibrinolysis, characterizing the remodeling of extracellular matrix (ECM). However, in established...... fibrosis, this two-way process is tipped towards fibrogenesis and this leads to a self-perpetuating accumulation of ECM, a distinct metabolic unit, together with other cells and processes promoting fibrosis deposition. Several mechanisms promote fibrosis regression, such as degradation of ECM, infiltration...

  9. Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Eiichiro Yamamoto

    Full Text Available The combination therapy of an angiotensin receptor blocker (ARB with a calcium channel blocker (CCB or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP were divided into 6 groups, and they were orally administered (1 vehicle, (2 olmesartan, an ARB, (3 azelnidipine, a CCB, (4 hydrochlorothiazide, a diuretic, (5 olmesartan combined with azelnidipine, or (6 olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

  10. Extraglandular and intraglandular vascularization of canine prostate.

    Science.gov (United States)

    Stefanov, Miroslav

    2004-03-01

    The literature on the vascularization of the canine prostate is reviewed and the clinical significance of prostate morphology is described. Scanning Electron Microscopy (SEM), combined with improved corrosion casting methods, reveal new morphological details that promise better diagnostics and treatment but also require expansion of clinical nomenclature. A proposal is made for including two previously unnamed veins in Nomina Anatomica Veterinaria (NAV). The canine prostate has two lobes with independent vascularization. Each lobe is supplied through the left and right a. prostatica, respectively. The a. prostatica sprouts three small vessels (cranial, middle, and caudal) towards the prostate gland. A. prostatica is a small-size artery whose wall structure is similar to the arteries of the muscular type. V. prostatica is a small-size valved vein. The canine prostate has capsular, parenchymal, and urethral vascular zones. The surface vessels of the capsule are predominantly veins and the diameter of arterial vessels is larger than that of the veins. The trabecular vessels are of two types: direct and branched. The prostate parenchyma is supplied by branches of the trabecular vessels. The periacinary capillaries are fenestrated and form a net in a circular pattern. The processes of the myoepithelial cells embrace both the acins and the periacinar capillaries. In the prostate ductal system. there are spermatozoa. The prostatic part of the urethra is supplied by an independent branch of a. prostatica. The prostatic urethral part is drained by v. prostatica, the vein of the urethral bulb and the ventral prostate veins. M. urethralis begins as early as the urethral prostatic part. The greater part of the white muscle fibers in m. urethralis suggest an enhanced anaerobic metabolism. Copyright 2004 Wiley-Liss, Inc.

  11. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

    Science.gov (United States)

    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  12. PDGFRα plays a crucial role in connective tissue remodeling.

    Science.gov (United States)

    Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

    2015-12-07

    Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

  13. PTH treatment activates intracortical bone remodeling in patients with hypoparathyroidism

    DEFF Research Database (Denmark)

    Sikjær, Tanja Tvistholm; Rejnmark, Lars; Thomsen, Jesper Skovhus

    2017-01-01

    Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high BMD. We have previously shown that hypoPT patients treated with PTH(1-84) for six months have highly increased bone turnover markers and a decrease in aBMD at the hip and spine(1). The present study aims...... to investigate the effect of PTH(1-84) on cortical bone and intracortical bone remodeling in hypoPT. The study was conducted on 20 transiliac bone biopsies from hypoPT patients after six months of treatment with either PTH(1-84) 100 µg s.c./day N=10 or placebo N=10. The groups were age- (±6 years) and gender...... and diameter were measured. Cortical porosity and pore density did not differ between groups, but PTH treatment had a marked effect on the remodeling status of the pores. The percentage of pores undergoing remodeling was higher in the PTH-group than in placebo-group reported as median values (IQR[25-75%]) (52...

  14. Remodeling of the methylation landscape in breast cancer metastasis.

    Directory of Open Access Journals (Sweden)

    Marsha Reyngold

    Full Text Available The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process.

  15. Computational bone remodelling simulations and comparisons with DEXA results.

    Science.gov (United States)

    Turner, A W L; Gillies, R M; Sekel, R; Morris, P; Bruce, W; Walsh, W R

    2005-07-01

    Femoral periprosthetic bone loss following total hip replacement is often associated with stress shielding. Extensive bone resorption may lead to implant or bone failure and complicate revision surgery. In this study, an existing strain-adaptive bone remodelling theory was modified and combined with anatomic three-dimensional finite element models to predict alterations in periprosthetic apparent density. The theory incorporated an equivalent strain stimulus and joint and muscle forces from 45% of the gait cycle. Remodelling was simulated for three femoral components with different design philosophies: cobalt-chrome alloy, two-thirds proximally coated; titanium alloy, one-third proximally coated; and a composite of cobalt-chrome surrounded by polyaryletherketone, fully coated. Theoretical bone density changes correlated significantly with clinical densitometry measurements (DEXA) after 2 years across the Gruen zones (R2>0.67, p<0.02), with average differences of less than 5.4%. The results suggest that a large proportion of adaptive bone remodelling changes seen clinically with these implants may be explained by a consistent theory incorporating a purely mechanical stimulus. This theory could be applied to pre-clinical testing of new implants, investigation of design modifications, and patient-specific implant selection.

  16. Remodeling sensory cortical maps implants specific behavioral memory.

    Science.gov (United States)

    Bieszczad, K M; Miasnikov, A A; Weinberger, N M

    2013-08-29

    Neural mechanisms underlying the capacity of memory to be rich in sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels the adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66-kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity was consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects' area of expansion and the tone that was strongest in each animal's memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Effects of aging and resistance training in rat tendon remodeling.

    Science.gov (United States)

    Marqueti, Rita C; Durigan, João L Q; Oliveira, Anderson José S; Mekaro, Marcelo Shinyu; Guzzoni, Vinicius; Aro, Andrea A; Pimentel, Edson Rosa; Selistre-de-Araujo, Heloisa S

    2018-01-01

    In elderly persons, weak tendons contribute to functional limitations, injuries, and disability, but resistance training can attenuate this age-related decline. We evaluated the effects of resistance training on the extracellular matrix (ECM) of the calcaneal tendon (CT) in young and old rats and its effect on tendon remodeling. Wistar rats aged 3 mo (young, n = 30) and 20 mo (old, n = 30) were divided into 4 groups: young sedentary, young trained, old sedentary (OS), and old trained (OT). The training sessions were conducted over a 12-wk period. Aging in sedentary rats showed down-regulation in key genes that regulated ECM remodeling. Moreover, the OS group showed a calcification focus in the distal region of the CT, with reduced blood vessel volume density. In contrast, resistance training was effective in up-regulating connective tissue growth factor, VEGF, and decorin gene expression in old rats. Resistance training also increased proteoglycan content in young and old rats in special small leucine-rich proteoglycans and blood vessels and prevented calcification in OT rats. These findings confirm that resistance training is a potential mechanism in the prevention of aging-related loss in ECM and that it attenuates the detrimental effects of aging in tendons, such as ruptures and tendinopathies.-Marqueti, R. C., Durigan, J. L. Q., Oliveira, A. J. S., Mekaro, M. S., Guzzoni, V., Aro, A. A., Pimentel, E. R., Selistre-de-Araujo, H. S. Effects of aging and resistance training in rat tendon remodeling. © FASEB.

  18. REMODELING SENSORY CORTICAL MAPS IMPLANTS SPECIFIC BEHAVIORAL MEMORY

    Science.gov (United States)

    Bieszczad, Kasia M.; Miasnikov, Alexandre A.; Weinberger, Norman M.

    2013-01-01

    Neural mechanisms underlying the capacity of memory to be rich with sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66 kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity were consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects’ area of expansion and the tone that was strongest in each animal’s memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation. PMID:23639876

  19. Pediatric interventional radiology: vascular interventions

    International Nuclear Information System (INIS)

    Kandasamy, Devasenathipathy; Gamanagatti, Shivanand; Gupta, Arun Kumar

    2016-01-01

    Pediatric interventional radiology (PIR) comprises a range of minimally invasive diagnostic and therapeutic procedures that are performed using image guidance. PIR has emerged as an essential adjunct to various surgical and medical conditions. Over the years, technology has undergone dramatic and continuous evolution, making this speciality grow. In this review, the authors will discuss various vascular interventional procedures undertaken in pediatric patients. It is challenging for the interventional radiologist to accomplish a successful interventional procedure. There are many vascular interventional radiology procedures which are being performed and have changed the way the diseases are managed. Some of the procedures are life saving and have become the treatment of choice in those patients. The future is indeed bright for the practice and practitioners of pediatric vascular and non-vascular interventions. As more and more of the procedures that are currently being performed in adults get gradually adapted for use in the pediatric population, it may be possible to perform safe and successful interventions in many of the pediatric vascular lesions that are otherwise being referred for surgery. (author)

  20. Preintervention lesion remodelling affects operative mechanisms of balloon optimised directional coronary atherectomy procedures: a volumetric study with three dimensional intravascular ultrasound

    Science.gov (United States)

    von Birgelen, C; Mintz, G; de Vrey, E A; Serruys, P; Kimura, T; Nobuyoshi, M; Popma, J; Leon, M; Erbel, R; de Feyter, P J

    2000-01-01

    AIMS—To classify atherosclerotic coronary lesions on the basis of adequate or inadequate compensatory vascular enlargement, and to examine changes in lumen, plaque, and vessel volumes during balloon optimised directional coronary atherectomy procedures in relation to the state of adaptive remodelling before the intervention.
DESIGN—29 lesion segments in 29 patients were examined with intravascular ultrasound before and after successful balloon optimised directional coronary atherectomy procedures, and a validated volumetric intravascular ultrasound analysis was performed off-line to assess the atherosclerotic lesion remodelling and changes in plaque and vessel volumes that occurred during the intervention. Based on the intravascular ultrasound data, lesions were classified according to whether there was inadequate (group I) or adequate (group II) compensatory enlargement.
RESULTS—There was no significant difference in patient and lesion characteristics between groups I and II (n = 10 and 19), including lesion length and details of the intervention. Quantitative coronary angiographic data were similar for both groups. However, plaque and vessel volumes were significantly smaller in group I than in II. In group I, 9 (4)% (mean (SD)) of the plaque volume was ablated, while in group II 16 (11)% was ablated (p = 0.01). This difference was reflected in a lower lumen volume gain in group I than in group II (46 (18) mm3 v 80 (49) mm3 (p atherectomy procedures. Plaque ablation was found to be particularly low in lesions with inadequate compensatory vascular enlargement.


Keywords: intravascular ultrasound; ultrasonics; remodelling; coronary artery disease; atherectomy PMID:10648496

  1. Fetal origin of vascular aging

    Directory of Open Access Journals (Sweden)

    Shailesh Pitale

    2011-01-01

    Full Text Available Aging is increasingly regarded as an independent risk factor for development of cardiovascular diseases such as atherosclerosis and hypertension and their complications (e.g. MI and Stroke. It is well known that vascular disease evolve over decades with progressive accumulation of cellular and extracellular materials and many inflammatory processes. Metabolic syndrome, obesity and diabetes are conventionally recognized as risk factors for development of coronary vascular disease (CVD. These conditions are known to accelerate ageing process in general and vascular ageing in particular. Adverse events during intrauterine life may programme organ growth and favour disease later in life, popularly known as, ′Barker′s Hypothesis′. The notion of fetal programming implies that during critical periods of prenatal growth, changes in the hormonal and nutritional milieu of the conceptus may alter the full expression of the fetal genome, leading to permanent effects on a range of physiological.

  2. Imaging after vascular gene therapy

    International Nuclear Information System (INIS)

    Manninen, Hannu I.; Yang, Xiaoming

    2005-01-01

    Targets for cardiovascular gene therapy currently include limiting restenosis after balloon angioplasty and stent placement, inhibiting vein bypass graft intimal hyperplasia/stenosis, therapeutic angiogenesis for cardiac and lower-limb ischemia, and prevention of thrombus formation. While catheter angiography is still standard method to follow-up vascular gene transfer, other modern imaging techniques, especially intravascular ultrasound (IVUS), magnetic resonance (MR), and positron emission tomography (PET) imaging provide complementary information about the therapeutic effect of vascular gene transfer in humans. Although molecular imaging of therapeutic gene expression in the vasculatures is still in its technical development phase, it has already offered basic medical science an extremely useful in vivo evaluation tool for non- or minimally invasive imaging of vascular gene therapy

  3. Immunohistochemical examination of plexiform-like complex vascular lesions in the lungs of broiler chickens selected for susceptibility to idiopathic pulmonary arterial hypertension.

    Science.gov (United States)

    Hamal, Krishna R; Erf, Gisela F; Anthony, Nicholas B; Wideman, Robert F

    2012-01-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, and by extensive vascular remodelling. In human IPAH patients, remodelling of the pulmonary vasculature results in the formation of plexiform lesions in the terminal pulmonary arterioles. Various molecules are expressed in the human plexiform lesions, including alpha smooth muscle actin, von Willebrand factor, vascular endothelial growth factor, vascular endothelial growth factor receptor type 2, hypoxia inducible factor-1α, survivin, tenascin, collagen, fibronectin, and various immune/inflammatory cells such as, cytotoxic lymphocytes, B lymphocytes, MHC class II cells, and monocytes/macrophages are also present. Plexiform lesions rarely develop in the lungs of laboratory animals, but plexiform-like complex vascular lesions (CVL) do develop spontaneously in the lungs of broiler chickens from an IPAH-susceptible line. To examine angioproliferative and immune-system-related activities associated with CVL in broiler lungs, paraformaldehyde-fixed, paraffin-embedded lung sections from 8-week-old to 24-week-old broiler chickens were stained immunohistochemically using monoclonal or polyclonal antibodies specific for angioproliferative molecules and immune/inflammatory cells. The CVL in the lungs of broiler chickens exhibited positive staining for both angioproliferative molecules and immune/inflammatory cells. These observations combined with the close histological resemblance of broiler CVL to the plexiform lesions of human IPAH patients further validates chickens from our IPAH-susceptible line as an excellent animal model of spontaneous plexogenic arteriopathy.

  4. Vascular Gene Expression: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Angélica Concepción eMartínez-Navarro

    2013-07-01

    Full Text Available The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a primitive vascular tissue (a lycophyte, as well as from others that lack a true vascular tissue (a bryophyte, and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non- vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

  5. STEREOLOGICAL STUDIES ON FETAL VASCULAR DEVELOPMENT IN HUMAN PLACENTAL VILLI

    Directory of Open Access Journals (Sweden)

    Terry M Mayhew

    2011-05-01

    Full Text Available In human pregnancy, fetal well-being depends on the development of placental villi and the creation and maintenance of fetal microvessels within them. The aim of this study was to define stereological measures of the growth, capillarization and maturation of villi and of fetoplacental angiogenesis and capillary remodelling. Placentas were collected at 12-41 weeks of gestation and assigned to six age groups spanning equal age ranges. Tissue samples were randomised for position and orientation. Overall growth of peripheral (intermediate and terminal villi and their capillaries was evaluated using total volumes, surface areas and lengths. Measures of villous capillarization comprised capillary volume, surface and length densities and capillary:villus surface and length ratios. Size and shape remodelling of villi and capillaries was assessed using mean cross-sectional areas, perimeters and shape coefficients (perimeter2/area. Group comparisons were drawn by analysis of variance. Villous and capillary volumes, surfaces and lengths increased significantly throughout gestation. Villous maturation involved phasic (capillary:villus surface and length ratios or progressive (volume, surface and length densities increases in indices of villous capillarization. It also involved isomorphic thinning (cross-sectional areas and perimeters declined but shape coefficients did not alter. In contrast, growth of capillaries did not involve changes in luminal areas or perimeters. The results show that villous growth and fetal angiogenesis involve increases in overall length rather than calibre and that villous differentiation involves increased capillarization. Although they do not distinguish between increases in the lengths versus numbers of capillary segments, other studies have shown that capillaries switch from branching to non-branching angiogenesis during gestation. Combined with maintenance of capillary calibres, these processes will contribute to the reduced

  6. [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.

  7. Vascular malforma- tions part 1 — normal and abnormal vascular ...

    African Journals Online (AJOL)

    Enrique

    to form the primitive vascular plexus. Angiogenesis is the formation of new vessels by sprouting or splitting of ... The differentiation of primitive vessels into arteries, veins or capillaries is determined by flow patterns .... identify, but it is probable that as time progresses further specific genetic defects related to the development ...

  8. 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

  9. Role of Renin-Angiotensin system and oxidative stress on vascular inflammation in insulin resistence model.

    Science.gov (United States)

    Renna, N F; Lembo, C; Diez, E; Miatello, R M

    2013-01-01

    (1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10(-3) mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

  10. Role of Renin-Angiotensin System and Oxidative Stress on Vascular Inflammation in Insulin Resistence Model

    Directory of Open Access Journals (Sweden)

    N. F. Renna

    2013-01-01

    Full Text Available (1 This study aims to demonstrate the causal involvement of renin angiotensin system (RAS and oxidative stress (OS on vascular inflammation in an experimental model of metabolic syndrome (MS achieved by fructose administration to spontaneously hypertensive rats (FFHR during 12 weeks. (2 Chronic treatment with candesartan (C (10 mg/kg per day for the last 6 weeks or 4OH-Tempol (T (10−3 mmol/L in drinking water for the last 6 weeks reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3 Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4 The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.

  11. Vasohibin inhibits angiogenic sprouting in vitro and supports vascular maturation processes in vivo

    International Nuclear Information System (INIS)

    Kern, Johann; Steurer, Michael; Gastl, Günther; Gunsilius, Eberhard; Untergasser, Gerold

    2009-01-01

    The murine homologue of human vasohibin (mVASH1), a putative antiangiogenic protein, was investigated for its effects on in vitro and in vivo angiogenesis. Cell growth and migration were analyzed in murine fibroblasts, smooth muscle cells and endothelial cells. Angiogenic sprouting was studied in human umbilical vein endothelial cells (HUVECs) in the spheroid sprouting assay. In vivo effects on blood vessel formation were investigated in the chorioallantoic membrane (CAM) assay and in the C57BL/6 melanoma xenograft model. Purified murine and human VASH1 protein induced apoptosis of murine fibroblasts in vitro, but not of vascular aortic smooth muscle cells (AoSMC) or endothelial cells. Adenoviral overexpression of murine and human VASH1 inhibited capillary sprouting of HUVECs in the spheroid assay. Administration of recombinant murine and human VASH1 inhibited growth of large vessels in the CAM assay and promoted the formation of a dense, fine vascular network. Murine VASH1-overexpressing B16F10 melanomas displayed a reduction in large vessels and vascular area. Moreover, tumors showed more microvessels that stained positive for the mural cell markers α-smooth muscle cell actin (ASMA) and proteoglycan (NG2). Our data imply that murine VASH1 causes angiogenic remodelling by inhibiting angiogenic sprouting and large vessel growth, thereby supporting the formation of a vascular bed consisting predominantly of mature microvessels

  12. Current Strategies for the Manufacture of Small Size Tissue Engineering Vascular Grafts

    Directory of Open Access Journals (Sweden)

    Michele Carrabba

    2018-04-01

    Full Text Available Occlusive arterial disease, including coronary heart disease (CHD and peripheral arterial disease (PAD, is the main cause of death, with an annual mortality incidence predicted to rise to 23.3 million worldwide by 2030. Current revascularization techniques consist of angioplasty, placement of a stent, or surgical bypass grafting. Autologous vessels, such as the saphenous vein and internal thoracic artery, represent the gold standard grafts for small-diameter vessels. However, they require invasive harvesting and are often unavailable. Synthetic vascular grafts represent an alternative to autologous vessels. These grafts have shown satisfactory long-term results for replacement of large- and medium-diameter arteries, such as the carotid or common femoral artery, but have poor patency rates when applied to small-diameter vessels, such as coronary arteries and arteries below the knee. Considering the limitations of current vascular bypass conduits, a tissue-engineered vascular graft (TEVG with the ability to grow, remodel, and repair in vivo presents a potential solution for the future of vascular surgery. Here, we review the different methods that research groups have been investigating to create TEVGs in the last decades. We focus on the techniques employed in the manufacturing process of the grafts and categorize the approaches as scaffold-based (synthetic, natural, or hybrid or self-assembled (cell-sheet, microtissue aggregation and bioprinting. Moreover, we highlight the attempts made so far to translate this new strategy from the bench to the bedside.

  13. XXXI LIAC Meeting on Vascular Research - Proceedings

    Directory of Open Access Journals (Sweden)

    L. Monteiro Rodrigues et al.

    2015-12-01

    Tecidos C.12 - Elastogenesis in a tissue-engineered heart valve specifically developed for the mitral position (RWTH Aachen University Speaker / Prelector Ricardo Moreira Key-note lecture 5 - Bi-layer polyurethane-extracellular matrix cardiac patch improves ischemic ventricular wall remodelling in a rat model (Pittsburgh U Antonio D'Amore 4st Session | Sessão 4 Innovation and Technology from Diagnostics to Therapeutics | Inovação e Tecnologia de Diagnóstico à Terapêutica Chairman / Moderador Philippe Charpiot Key-note lecture 6 - SClinical and experimental potential of the noninvasive quantification of myocardial perfusion entropy by nuclear imaging (U Grenoble Laurent Riou C.13 - Hemorheology and Vascular Diseases (IMM, U Lisboa Speaker / Prelector Carlota Saldanha C.14 - Galectin 3 levels after running – a systematic review and perspective (Hospital Center of Vila Nova de Gaia/Espinho Speaker / Prelector Eduardo Vilela 4st Session | Sessão 4 Innovation and Technology from Diagnostics to Therapeutics | Inovação e Tecnologia de Diagnóstico à Terapêutica C.15 - Physiological computing: using vascular signals for something completely different (IBEB, U Lisboa Speaker / Prelector Hugo Ferreira Key-note lecture 7 - Opportunities for Direct Digital Manufacturing in Vascular Research (PU Leiria, CDRSP Geoffrey Mitchell 5st Session | Sessão 5 Clinical Applications | Aplicações Clínicas Chairman / Moderador Vicenta Llorente-Cortés C.16 - Identification of differentially expressed proteins in atherosclerotic patients with type 2 diabetes (U Sassari Speaker / Prelector Antonio Leppeda C.17 - Comparing the oscillatory properties of the LDF signal recorded from subjects with different ages during a passive leg raising test Speaker / Prelector Henrique Silva 5st Session | Sessão 5 Clinical Applications | Aplicações Clínicas C.18 - Endothelium-dependent vasoactivity of the human internal mammary artery: the influence of cardiovascular risk factors (FF, U Coimbra

  14. Proangiogenic hematopoietic cells of monocytic origin: roles in vascular regeneration and pathogenic processes of systemic sclerosis.

    Science.gov (United States)

    Yamaguchi, Yukie; Kuwana, Masataka

    2013-02-01

    New blood vessel formation is critical, not only for organ development and tissue regeneration, but also for various pathologic processes, such as tumor development and vasculopathy. The maintenance of the postnatal vascular system requires constant remodeling, which occurs through angiogenesis, vasculogenesis, and arteriogenesis. Vasculogenesis is mediated by the de novo differentiation of mature endothelial cells from endothelial progenitor cells (EPCs). Early studies provided evidence that bone marrow-derived CD14⁺ monocytes can serve as a subset of EPCs because of their expression of endothelial markers and ability to promote neovascularization in vitro and in vivo. However, the current consensus is that monocytic cells do not give rise to endothelial cells in vivo, but function as support cells, by promoting vascular formation and repair through their immediate recruitment to the site of vascular injury, secretion of proangiogenic factors, and differentiation into mural cells. These monocytes that function in a supporting role in vascular repair are now termed monocytic pro-angiogenic hematopoietic cells (PHCs). Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by excessive fibrosis and microvasculopathy, along with poor vascular formation and repair. We recently showed that in patients with SSc, circulating monocytic PHCs increase dramatically and have enhanced angiogenic potency. These effects may be induced in response to defective vascular repair machinery. Since CD14⁺ monocytes can also differentiate into fibroblast-like cells that produce extracellular matrix proteins, here we propose a new hypothesis that aberrant monocytic PHCs, once mobilized into circulation, may also contribute to the fibrotic process of SSc.

  15. Composite vascular grafts with high cell infiltration by co-electrospinning

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Zhikai, E-mail: tanzk@hnu.edu.cn; Wang, Hongjie; Gao, Xiangkai; Liu, Tong; Tan, Yongjun

    2016-10-01

    There is an increasing demand for functional small-diameter vascular grafts (diameter < 6 mm) to be used in clinical arterial replacement. An ideal vascular graft should have appropriate biomechanical properties and be biocompatible. Electrospinning has become a popular polymer processing technique for vascular tissue engineering, but the grafts fabricated by electrospinning often have relatively small pores and low porosity, which limit cell infiltration into scaffolds and hinder the regeneration and remodeling of grafts. In the present study, we aimed to develop an efficient method to prepare electrospun composite vascular grafts comprising natural and synthetic materials. We fabricated grafts made of polycaprolactone, gelatin, and polyvinyl alcohol (PVA) by co-electrospinning, and the scaffolds were further functionalized by immobilizing heparin on them. The PVA fibers degraded rapidly in vivo and generated electrospun scaffolds with high porosity, which significantly enhanced cell proliferation and infiltration. The mechanical properties of the grafts are suitable for use in artery replacement. Heparin functionalization of the grafts yielded a good antithrombogenic effect, which was demonstrated in platelet adhesion tests. Moreover, in vitro and in vivo results demonstrated that the heparin release from the grafts enhanced the growth of endothelial cells, which is important for the endothelium of implanted grafts. The results of this study indicate that our method is effective and controllable for the fabrication of vascular grafts that meet the clinical requirements for blood vessel transplantation. - Highlights: • This study indicate an effective method for the fabrication of vascular grafts that meet the clinical requirements. • Co-electrospinning were used to fabricate grafts made of polycaprolactone (PCL), gelatin (GT), and polyvinyl alcohol (PVA). • PVA was used to create large pores within the hybrid scaffolds, thereby enhancing cell infiltration

  16. Composite vascular grafts with high cell infiltration by co-electrospinning

    International Nuclear Information System (INIS)

    Tan, Zhikai; Wang, Hongjie; Gao, Xiangkai; Liu, Tong; Tan, Yongjun

    2016-01-01

    There is an increasing demand for functional small-diameter vascular grafts (diameter < 6 mm) to be used in clinical arterial replacement. An ideal vascular graft should have appropriate biomechanical properties and be biocompatible. Electrospinning has become a popular polymer processing technique for vascular tissue engineering, but the grafts fabricated by electrospinning often have relatively small pores and low porosity, which limit cell infiltration into scaffolds and hinder the regeneration and remodeling of grafts. In the present study, we aimed to develop an efficient method to prepare electrospun composite vascular grafts comprising natural and synthetic materials. We fabricated grafts made of polycaprolactone, gelatin, and polyvinyl alcohol (PVA) by co-electrospinning, and the scaffolds were further functionalized by immobilizing heparin on them. The PVA fibers degraded rapidly in vivo and generated electrospun scaffolds with high porosity, which significantly enhanced cell proliferation and infiltration. The mechanical properties of the grafts are suitable for use in artery replacement. Heparin functionalization of the grafts yielded a good antithrombogenic effect, which was demonstrated in platelet adhesion tests. Moreover, in vitro and in vivo results demonstrated that the heparin release from the grafts enhanced the growth of endothelial cells, which is important for the endothelium of implanted grafts. The results of this study indicate that our method is effective and controllable for the fabrication of vascular grafts that meet the clinical requirements for blood vessel transplantation. - Highlights: • This study indicate an effective method for the fabrication of vascular grafts that meet the clinical requirements. • Co-electrospinning were used to fabricate grafts made of polycaprolactone (PCL), gelatin (GT), and polyvinyl alcohol (PVA). • PVA was used to create large pores within the hybrid scaffolds, thereby enhancing cell infiltration

  17. [Vascular access guidelines for hemodialysis].

    Science.gov (United States)

    Rodríguez Hernández, J A; González Parra, E; Julián Gutiérrez, J M; Segarra Medrano, A; Almirante, B; Martínez, M T; Arrieta, J; Fernández Rivera, C; Galera, A; Gallego Beuter, J; Górriz, J L; Herrero, J A; López Menchero, R; Ochando, A; Pérez Bañasco, V; Polo, J R; Pueyo, J; Ruiz, Camps I; Segura Iglesias, R

    2005-01-01

    Quality of vascular access (VA) has a remarkable influence in hemodialysis patients outcomes. Dysfunction of VA represents a capital cause of morbi-mortality of these patients as well an increase in economical. Spanish Society of Neprhology, aware of the problem, has decided to carry out a revision of the issue with the aim of providing help in comprehensión and treatment related with VA problems, and achieving an homogenization of practices in three mayor aspects: to increase arteriovenous fistula utilization as first vascular access, to increment vascular access monitoring practice and rationalise central catheters use. We present a consensus document elaborated by a multidisciplinar group composed by nephrologists, vascular surgeons, interventional radiologysts, infectious diseases specialists and nephrological nurses. Along six chapters that cover patient education, creation of VA, care, monitoring, complications and central catheters, we present the state of the art and propose guidelines for the best practice, according different evidence based degrees, with the intention to provide help at the professionals in order to make aproppiate decissions. Several quality standars are also included.

  18. Image Quality in Vascular Radiology

    International Nuclear Information System (INIS)

    Vanhavere, F.; Struelens, L.

    2005-01-01

    In vascular radiology, the radiologists use the radiological image to diagnose or treat a specific vascular structure. From literature, we know that related doses are high and that large dose variability exists between different hospitals. The application of the optimization principle is therefore necessary and is obliged by the new legislation. So far, very little fieldwork has been performed and no practical instructions are available to do the necessary work. It's indisputable that obtaining quantitative data is of great interest for optimization purposes. In order to gain insight into these doses and the possible measures for dose reduction, we performed a comparative study in 7 hospitals. Patient doses will be measured and calculated for specific procedures in vascular radiology and evaluated against their most influencing parameters. In view of optimization purposes, a protocol for dose audit will be set-up. From the results and conclusions in this study, experimentally based guidelines will be proposed, in order to improve clinical practice in vascular radiology

  19. Vascular aspects of multiple sclerosis

    NARCIS (Netherlands)

    D'haeseleer, Miguel; Cambron, Melissa; Vanopdenbosch, Ludo; De Keyser, Jacques

    Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial

  20. The Chd1 Chromatin Remodeler Shifts Nucleosomal DNA Bidirectionally as a Monomer

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Yupeng; Levendosky, Robert F.; Chakravarthy, Srinivas; Patel, Ashok; Bowman, Gregory D.; Myong, Sua

    2017-10-01

    Chromatin remodelers catalyze dynamic packaging of the genome by carrying out nucleosome assembly/disassembly, histone exchange, and nucleosome repositioning. Remodeling results in evenly spaced nucleosomes, which requires probing both sides of the nucleosome, yet the way remodelers organize sliding activity to achieve this task is not understood. Here, we show that the monomeric Chd1 remodeler shifts DNA back and forth by dynamically alternating between different segments of the nucleosome. During sliding, Chd1 generates unstable remodeling intermediates that spontaneously relax to a pre-remodeled position. We demonstrate that nucleosome sliding is tightly controlled by two regulatory domains: the DNA-binding domain, which interferes with sliding when its range is limited by a truncated linking segment, and the chromodomains, which play a key role in substrate discrimination. We propose that active interplay of the ATPase motor with the regulatory domains may promote dynamic nucleosome structures uniquely suited for histone exchange and chromatin reorganization during transcription.

  1. Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

    DEFF Research Database (Denmark)

    Østrup, Olga; Hyttel, Poul; Klærke, Dan Arne

    2011-01-01

    Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression....... This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling...... and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation...

  2. Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis

    Directory of Open Access Journals (Sweden)

    F. Aura Kullmann

    2018-04-01

    Full Text Available Interstitial cystitis/bladder pain syndrome (IC/BPS is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunn’s nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons, in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a “sensory network” and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans

  3. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling.

    Science.gov (United States)

    Walters, Tomos E; Kalman, Jonathan M; Patel, Sheila K; Mearns, Megan; Velkoska, Elena; Burrell, Louise M

    2017-08-01

    Angiotensin converting enzyme 2 (ACE2) is an integral membrane protein whose main action is to degrade angiotensin II. Plasma ACE2 activity is increased in various cardiovascular diseases. We aimed to determine the relationship between plasma ACE2 activity and human atrial fibrillation (AF), and in particular its relationship to left atrial (LA) structural remodelling. One hundred and three participants from a tertiary arrhythmia centre, including 58 with paroxysmal AF (PAF), 20 with persistent AF (PersAF), and 25 controls, underwent clinical evaluation, echocardiographic analysis, and measurement of plasma ACE2 activity. A subgroup of 20 participants underwent invasive LA electroanatomic mapping. Plasma ACE2 activity levels were increased in AF [control 13.3 (9.5-22.3) pmol/min/mL; PAF 16.9 (9.7-27.3) pmol/min/mL; PersAF 22.8 (13.7-33.4) pmol/min/mL, P = 0.006]. Elevated plasma ACE2 was associated with older age, male gender, hypertension and vascular disease, elevated left ventricular (LV) mass, impaired LV diastolic function and advanced atrial disease (P < 0.05 for all). Independent predictors of elevated plasma ACE2 activity were AF (P = 0.04) and vascular disease (P < 0.01). There was a significant relationship between elevated ACE2 activity and low mean LA bipolar voltage (adjusted R2 = 0.22, P = 0.03), a high proportion of complex fractionated electrograms (R2 = 0.32, P = 0.009) and a long LA activation time (R2 = 0.20, P = 0.04). Plasma ACE2 activity is elevated in human AF. Both AF and vascular disease predict elevated plasma ACE2 activity, and elevated plasma ACE2 is significantly associated with more advanced LA structural remodelling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  4. Soft skills turned into hard facts: nucleosome remodelling at developmental switches.

    Science.gov (United States)

    Chioda, M; Becker, P B

    2010-07-01

    Nucleosome remodelling factors are regulators of DNA accessibility in chromatin and lubricators of all major functions of eukaryotic genomes. Their action is transient and reversible, yet can be decisive for irreversible cell-fate decisions during development. In addition to the well-known local actions of nucleosome remodelling factors during transcription initiation, more global and fundamental roles for remodelling complexes in shaping the epigenome during development are emerging.

  5. Remodeling of the postsynaptic plasma membrane during neural development.

    Science.gov (United States)

    Tulodziecka, Karolina; Diaz-Rohrer, Barbara B; Farley, Madeline M; Chan, Robin B; Di Paolo, Gilbert; Levental, Kandice R; Waxham, M Neal; Levental, Ilya

    2016-11-07

    Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse. © 2016 Tulodziecka et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  6. Subclinical hypothyroidism after vascular complicated pregnancy

    NARCIS (Netherlands)

    Zanden, M. van der; Hop-de Groot, R.J.; Sweep, F.C.; Ross, H.A.; Heijer, M. den; Spaanderman, M.E.A.

    2013-01-01

    OBJECTIVE: Women with a history of vascular complicated pregnancy are at risk for developing remote cardiovascular disease. It is associated with underlying cardiovascular risk factors both jeopardizing trophoblast and vascular function. Subclinical hypothyroidism may relate to both conditions.

  7. Pediatric central nervous system vascular malformations

    International Nuclear Information System (INIS)

    Burch, Ezra A.; Orbach, Darren B.

    2015-01-01

    Pediatric central nervous system (CNS) vascular anomalies include lesions found only in the pediatric population and also the full gamut of vascular lesions found in adults. Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some CNS vascular lesions that occur in adults, such as arteriovenous malformation, have somewhat distinct manifestations in children, and those are also discussed. Additionally, children with CNS vascular malformations often have associated broader vascular conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia, and capillary malformation-arteriovenous malformation syndrome (related to the RASA1 mutation). The treatment of pediatric CNS vascular malformations has greatly benefited from advances in endovascular therapy, including technical advances in adult interventional neuroradiology. Dramatic advances in therapy are expected to stem from increased understanding of the genetics and vascular biology that underlie pediatric CNS vascular malformations. (orig.)

  8. Pediatric central nervous system vascular malformations

    Energy Technology Data Exchange (ETDEWEB)

    Burch, Ezra A. [Brigham and Women' s Hospital, Department of Radiology, Boston, MA (United States); Orbach, Darren B. [Boston Children' s Hospital, Neurointerventional Radiology, Boston, MA (United States)

    2015-09-15

    Pediatric central nervous system (CNS) vascular anomalies include lesions found only in the pediatric population and also the full gamut of vascular lesions found in adults. Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some CNS vascular lesions that occur in adults, such as arteriovenous malformation, have somewhat distinct manifestations in children, and those are also discussed. Additionally, children with CNS vascular malformations often have associated broader vascular conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia, and capillary malformation-arteriovenous malformation syndrome (related to the RASA1 mutation). The treatment of pediatric CNS vascular malformations has greatly benefited from advances in endovascular therapy, including technical advances in adult interventional neuroradiology. Dramatic advances in therapy are expected to stem from increased understanding of the genetics and vascular biology that underlie pediatric CNS vascular malformations. (orig.)

  9. ESRD QIP - Vascular Access - Payment Year 2018

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset includes facility details, performance rates, vascular access topic measure score, and the state and national average measure scores for the vascular...

  10. Performance evaluation on cool roofs for green remodeling

    Science.gov (United States)

    Yun, Yosun; Cho, Dongwoo; Cho, Kyungjoo

    2018-06-01

    Cool roofs refer that maximize heat emission, and minimize the absorption of solar radiation energy, by applying high solar reflectance paints, or materials to roofs or rooftops. The application of cool roofs to existing buildings does not need to take structural issues into consideration, as rooftop greening, is an alternative that can be applied to existing buildings easily. This study installed a cool roofs on existing buildings, and evaluated the performances, using the results to propose certification standards for green remodeling, considering the cool roof-related standards.

  11. Expression of RANKL/OPG during bone remodeling in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, H., E-mail: tnk@ymghp.jp [Department of Orthopedic Surgery, Yamaguchi Grand Medical Center, 77 Ohsaki, Hofu, Yamaguchi 747-8511 (Japan); Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 (United States); Mine, T. [Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505 (Japan); Ogasa, H. [Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 (United States); Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505 (Japan); Taguchi, T. [Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505 (Japan); Liang, C.T. [Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 (United States); National Health Research Institutes, Taipei 115, Taiwan (China)

    2011-08-12

    Highlights: {yields} This is the first study to determine the relationship between osteogenic differentiation and RANKL/OPG expression during bone remodeling in vivo. {yields} The OPG expression peak occurred during the bone formation phase, whereas the marked elevation of RANKL expression was observed during the bone resorption phase. {yields} Histological analysis showed that RANKL/OPG immunoreactivity was predominantly associated with bone marrow cells in the marrow cavity. {yields} The present study confirmed that RANKL/OPG are key factors linking bone formation to resorption during the bone remodeling process. -- Abstract: The interaction between receptor activator of nuclear factor {kappa}B ligand (RANKL) and osteoprotegerin (OPG) plays a dominant role in osteoclastogenesis. As both proteins are produced by osteoblast lineage cells, they are considered to represent a key link between bone formation and resorption. In this study, we investigated the expression of RANKL and OPG during bone remodeling in vivo to determine the relationship between osteoclastogenic stimulation and osteoblastic differentiation. Total RNA was prepared from rat femurs after marrow ablation on days 0, 3, 6, and 9. The temporal activation patterns of osteoblast-related genes (procollagen {alpha}1 (I), alkaline phosphatase, osteopontin, and osteocalcin) were examined by Northern blot analysis. An appreciable increase in the expression of these osteoblast markers was observed on day 3. The peak increase in gene expression was observed on day 6 followed by a slight reduction by day 9. Real-time PCR analysis showed that the OPG mRNA expression was markedly upregulated on day 6 and slightly decreased on day 9. In contrast, RANKL mRNA expression was increased by more than 20-fold on day 9. The RANKL/OPG ratio, an index of osteoclastogenic stimulation, peaked on day 9. Histological analysis showed that RANKL and OPG immunoreactivity were predominantly associated with bone marrow cells. The

  12. Expression of RANKL/OPG during bone remodeling in vivo

    International Nuclear Information System (INIS)

    Tanaka, H.; Mine, T.; Ogasa, H.; Taguchi, T.; Liang, C.T.

    2011-01-01

    Highlights: → This is the first study to determine the relationship between osteogenic differentiation and RANKL/OPG expression during bone remodeling in vivo. → The OPG expression peak occurred during the bone formation phase, whereas the marked elevation of RANKL expression was observed during the bone resorption phase. → Histological analysis showed that RANKL/OPG immunoreactivity was predominantly associated with bone marrow cells in the marrow cavity. → The present study confirmed that RANKL/OPG are key factors linking bone formation to resorption during the bone remodeling process. -- Abstract: The interaction between receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) plays a dominant role in osteoclastogenesis. As both proteins are produced by osteoblast lineage cells, they are considered to represent a key link between bone formation and resorption. In this study, we investigated the expression of RANKL and OPG during bone remodeling in vivo to determine the relationship between osteoclastogenic stimulation and osteoblastic differentiation. Total RNA was prepared from rat femurs after marrow ablation on days 0, 3, 6, and 9. The temporal activation patterns of osteoblast-related genes (procollagen α1 (I), alkaline phosphatase, osteopontin, and osteocalcin) were examined by Northern blot analysis. An appreciable increase in the expression of these osteoblast markers was observed on day 3. The peak increase in gene expression was observed on day 6 followed by a slight reduction by day 9. Real-time PCR analysis showed that the OPG mRNA expression was markedly upregulated on day 6 and slightly decreased on day 9. In contrast, RANKL mRNA expression was increased by more than 20-fold on day 9. The RANKL/OPG ratio, an index of osteoclastogenic stimulation, peaked on day 9. Histological analysis showed that RANKL and OPG immunoreactivity were predominantly associated with bone marrow cells. The expression of bone formation

  13. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    Science.gov (United States)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

  14. Altered thermogenesis and impaired bone remodeling in Misty mice.

    Science.gov (United States)

    Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E; Bornstein, Sheila A; Le, Phuong; Kawai, Masanobu; Lotinun, Sutada; Horowitz, Mark C; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

    2013-09-01

    Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a, and less sympathetic innervation compared to wild-type (+/ +)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hours), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2, and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wild-type. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wild-type and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular bone volume/total volume (BV/TV) loss in the distal femur of Misty mice without affecting wild-type. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold

  15. REMOD: a computational tool for remodeling neuronal dendrites

    Directory of Open Access Journals (Sweden)

    Panagiotis Bozelos

    2014-05-01

    Full Text Available In recent years, several modeling studies have indicated that dendritic morphology is a key determinant of how individual neurons acquire a unique signal processing profile. The highly branched dendritic structure that originates from the cell body, explores the surrounding 3D space in a fractal-like manner, until it reaches a certain amount of complexity. Its shape undergoes significant alterations not only in various neuropathological conditions, but in physiological, too. Yet, despite the profound effect that these alterations can have on neuronal function, the causal relationship between structure and function remains largely elusive. The lack of a systematic approach for remodeling neuronal cells and their dendritic trees is a key limitation that contributes to this problem. In this context, we developed a computational tool that allows the remodeling of any type of neurons, given a set of exemplar morphologies. The tool is written in Python and provides a simple GUI that guides the user through various options to manipulate selected neuronal morphologies. It provides the ability to load one or more morphology files (.swc or .hoc and choose specific dendrites to operate one of the following actions: shrink, remove, extend or branch (as shown in Figure 1. The user retains complete control over the extent of each alteration and if a chosen action is not possible due to pre-existing structural constraints, appropriate warnings are produced. Importantly, the tool can also be used to extract morphology statistics for one or multiple morphologies, including features such as the total dendritic length, path length to the root, branch order, diameter tapering, etc. Finally, an experimental utility enables the user to remodel entire dendritic trees based on preloaded statistics from a database of cell-type specific neuronal morphologies. To our knowledge, this is the first tool that allows (a the remodeling of existing –as opposed to the de novo

  16. ATP-Dependent Chromatin Remodeling Factors and Their Roles in Affecting Nucleosome Fiber Composition

    Directory of Open Access Journals (Sweden)

    Alexandra Lusser

    2011-10-01

    Full Text Available ATP-dependent chromatin remodeling factors of the SNF2 family are key components of the cellular machineries that shape and regulate chromatin structure and function. Members of this group of proteins have broad and heterogeneous functions ranging from controlling gene activity, facilitating DNA damage repair, promoting homologous recombination to maintaining genomic stability. Several chromatin remodeling factors are critical components of nucleosome assembly processes, and recent reports have identified specific functions of distinct chromatin remodeling factors in the assembly of variant histones into chromatin. In this review we will discuss the specific roles of ATP-dependent chromatin remodeling factors in determining nucleosome composition and, thus, chromatin fiber properties.

  17. Self-assembly of the general membrane-remodeling protein PVAP into sevenfold virus-associated pyramids.

    Science.gov (United States)

    Daum, Bertram; Quax, Tessa E F; Sachse, Martin; Mills, Deryck J; Reimann, Julia; Yildiz, Özkan; Häder, Sabine; Saveanu, Cosmin; Forterre, Patrick; Albers, Sonja-Verena; Kühlbrandt, Werner; Prangishvili, David

    2014-03-11

    Viruses have developed a wide range of strategies to escape from the host cells in which they replicate. For egress some archaeal viruses use a pyramidal structure with sevenfold rotational symmetry. Virus-associated pyramids (VAPs) assemble in the host cell membrane from the virus-encoded protein PVAP and open at the end of the infection cycle. We characterize this unusual supramolecular assembly using a combination of genetic, biochemical, and electron microscopic techniques. By whole-cell electron cryotomography, we monitored morphological changes in virus-infected host cells. Subtomogram averaging reveals the VAP structure. By heterologous expression of PVAP in cells from all three domains of life, we demonstrate that the protein integrates indiscriminately into virtually any biological membrane, where it forms sevenfold pyramids. We identify the protein domains essential for VAP formation in PVAP truncation mutants by their ability to remodel the cell membrane. Self-assembly of PVAP into pyramids requires at least two different, in-plane and out-of-plane, protein interactions. Our findings allow us to propose a model describing how PVAP arranges to form sevenfold pyramids and suggest how this small, robust protein may be used as a general membrane-remodeling system.

  18. A Novel Mammary Fat Pad Transplantation Technique to Visualize the Vessel Generation of Vascular Endothelial Stem Cells.

    Science.gov (United States)

    Yu, Qing Cissy; Song, Wenqian; Lai, Dengwen; Zeng, Yi Arial

    2017-08-03

    Endothelial cells (ECs) are the fundamental building blocks of the vascular architecture and mediate vascular growth and remodeling to ensure proper vessel development and homeostasis. However, studies on endothelial lineage hierarchy remain elusive due to the lack of tools to gain access as well as to directly evaluate their behavior in vivo. To address this shortcoming, a new tissue model to study angiogenesis using the mammary fat pad has been developed. The mammary gland develops mostly in the postnatal stages, including puberty and pregnancy, during which robust epithelium proliferation is accompanied by extensive vascular remodeling. Mammary fat pads provide space, matrix, and rich angiogenic stimuli from the growing mammary epithelium. Furthermore, mammary fat pads are located outside the peritoneal cavity, making them an easily accessible grafting site for assessing the angiogenic potential of exogenous cells. This work also describes an efficient tracing approach using fluorescent reporter mice to specifically label the targeted population of vascular endothelial stem cells (VESCs) in vivo. This lineage tracing method, coupled with subsequent tissue whole-mount microscopy, enable the direct visualization of targeted cells and their descendants, through which the proliferation capability can be quantified and the differentiation commitment can be fate-mapped. Using these methods, a population of bipotent protein C receptor (Procr) expressing VESCs has recently been identified in multiple vascular systems. Procr + VESCs, giving rise to both new ECs and pericytes, actively contribute to angiogenesis during development, homeostasis, and injury repair. Overall, this manuscript describes a new mammary fat pad transplantation and in vivo lineage tracing techniques that can be used to evaluate the stem cell properties of VESCs.

  19. 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.

  20. Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Gang [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Hitomi, Hirofumi, E-mail: hitomi@kms.ac.jp [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Hosomi, Naohisa [Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa (Japan); Lei, Bai; Nakano, Daisuke [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Deguchi, Kazushi; Mori, Hirohito; Masaki, Tsutomu [Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Ma, Hong [Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Griendling, Kathy K. [Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (United States); Nishiyama, Akira [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan)

    2011-10-15

    Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. -- Highlights: {yields} Mechanical stretch augments insulin-induced VSMC proliferation via IGF-1 receptor. {yields} Src/EGFR-mediated ERK and Akt phosphorylation are augmented in stretched VSMCs. {yields} Similar to in vitro experiment, IGF-1 receptor is increased in hypertensive rats. {yields} Results provide possible mechanisms of vascular remodeling in hypertension with DM.

  1. Time-Series Interactions of Gene Expression, Vascular Growth and Hemodynamics during Early Embryonic Arterial Development.

    Directory of Open Access Journals (Sweden)

    Selda Goktas

    Full Text Available The role of hemodynamic forces within the embryo as biomechanical regulators for cardiovascular morphogenesis, growth, and remodeling is well supported through the experimental studies. Furthermore, clinical experience suggests that perturbed flow disrupts the normal vascular growth process as one etiology for congenital heart diseases (CHD and for fetal adaptation to CHD. However, the relationships between hemodynamics, gene expression and embryonic vascular growth are poorly defined due to the lack of concurrent, sequential in vivo data. In this study, a long-term, time-lapse optical coherence tomography (OCT imaging campaign was conducted to acquire simultaneous blood velocity, pulsatile micro-pressure and morphometric data for 3 consecutive early embryonic stages in the chick embryo. In conjunction with the in vivo growth and hemodynamics data, in vitro reverse transcription polymerase chain reaction (RT-PCR analysis was performed to track changes in transcript expression relevant to histogenesis and remodeling of the embryonic arterial wall. Our non-invasive extended OCT imaging technique for the microstructural data showed continuous vessel growth. OCT data coupled with the PIV technique revealed significant but intermitted increases in wall shear stress (WSS between first and second assigned stages and a noticeable decrease afterwards. Growth rate, however, did not vary significantly throughout the embryonic period. Among all the genes studied, only the MMP-2 and CASP-3 expression levels remained unchanged during the time course. Concurrent relationships were obtained among the transcriptional modulation of the genes, vascular growth and hemodynamics-related changes. Further studies are indicated to determine cause and effect relationships and reversibility between mechanical and molecular regulation of vasculogenesis.

  2. Basic Components of Vascular Connective Tissue and Extracellular Matrix.

    Science.gov (United States)

    Halper, Jaroslava

    2018-01-01

    Though the composition of the three layers constituting the blood vessel wall varies among the different types of blood vessels, and some layers may even be missing in capillaries, certain basic components, and properties are shared by all blood vessels, though each histologically distinct layer contains a unique complement of extracellular components, growth factors and cytokines, and cell types as well. The structure and composition of vessel layers informs and is informed by the function of the particular blood vessel. The adaptation of the composition and the resulting function of the extracellular matrix (ECM) to changes in circulation/blood flow and a variety of other extravascular stimuli can be characterized as remodeling spearheaded by vascular cells. There is a surprising amount of cell traffic among the three layers. It starts with endothelial cell mediated transmigration of inflammatory cells from the bloodstream into the subendothelium, and then into tissue adjoining the blood vessel. Smooth muscle cells and a variety of adventitial cells reside in tunica media and tunica externa, respectively. The latter cells are a mixture of progenitor/stem cells, fibroblasts, myofibroblasts, pericytes, macrophages, and dendritic cells and respond to endothelial injury by transdifferentiation as they travel into the two inner layers, intima and media for corrective mission in the ECM composition. This chapter addresses the role of various vascular cell types and ECM components synthesized by them in maintenance of normal structure and in their contribution to major pathological processes, such as atherosclerosis, organ fibrosis, and diabetic retinopathy. © 2018 Elsevier Inc. All rights reserved.

  3. Prefabrication of axial vascularized tissue engineering coral bone by an arteriovenous loop: a better model.

    Science.gov (United States)

    Dong, Qing-shan; Shang, Hong-tao; Wu, Wei; Chen, Fu-lin; Zhang, Jun-rui; Guo, Jia-ping; Mao, Tian-qiu

    2012-08-01

    The most important problem for the survival of thick 3-dimensional tissues is the lack of vascularization in the context of bone tissue engineering. In this study, a modified arteriovenous loop (AVL) was developed to prefabricate an axial vascularized tissue engineering coral bone in rabbit, with comparison of the arteriovenous bundle (AVB) model. An arteriovenous fistula between rabbit femoral artery and vein was anastomosed to form an AVL. It was placed in a circular side groove of the coral block. The complex was wrapped with an expanded-polytetrafluoroethylene membrane and implanted beneath inguinal skin. After 2, 4, 6 and 8 weeks, the degree of vascularization was evaluated by India ink perfusion, histological examination, vascular casts, and scanning electron microscopy images of vascular endangium. Newly formed fibrous tissues and vasculature extended over the surfaces and invaded the interspaces of entire coral block. The new blood vessels robustly sprouted from the AVL. Those invaginated cavities in the vascular endangium from scanning electron microscopy indicated vessel's sprouted pores. Above indexes in AVL model are all superior to that in AVB model, indicating that the modified AVL model could more effectively develop vascularization in larger tissue engineering bone. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function

    Science.gov (United States)

    Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

    2016-01-01

    The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo. DOI: http://dx.doi.org/10.7554/eLife.13450.001 PMID:27130520

  5. Circadian expression profiles of chromatin remodeling factor genes in Arabidopsis.

    Science.gov (United States)

    Lee, Hong Gil; Lee, Kyounghee; Jang, Kiyoung; Seo, Pil Joon

    2015-01-01

    The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock.

  6. Observations of super early left ventricular remodeling experimental myocardial infarction

    International Nuclear Information System (INIS)

    Zhang, C.G.; Jin, J.H.; Zhao, X.B.; Kang, C.S.; Liang, F.Y.; Yin, Z.M.; Liu, G.F.; Li, S.J.; Li, X.F.; Hu, G.; Qin, D.Z.; Song, L.Z.

    2004-01-01

    Purpose: Ventricular remodeling is defined as the changes in the shape and size of the entire left ventricle after acute myocardial infarction (AMI). Many investigators have shown that left ventricular remodeling is related to clinical outcomes, including mortality, that represent the natural history, of the heart failure syndrome. The aim of this study was to demonstrate that it is possible to observe super early left ventricular remodeling by 99mTc-MIBI myocardial imaging in the dog model of acute experimental myocardial infarction. Methods: Experimental subjects: Twenty-three healthy mongrel dogs (14-25 kg) of either sex were studied under general anesthesia (sodium pentobarbital, 30 mg/kg). The left anterior descending (LAD) coronary artery was dissected and ligated between the first and second diagonal branches. Seven dogs died of ventricular fibrillation after the LAD coronary artery ligation. The 16 remaining dogs were divided into two groups: Group A (GA) received 99mTc-MIBI myocardial imaging (n=8): Group B (GB) received 99mTc-MIBI myocardial imaging combined with echocardiography (n=8). 99mTc-MIBI myocardial perfusion imaging :Static 99mTc-MIBI myocardial imaging was taken with ADAC Vertex Dual-head SPECT. 99mTc-MIBI kit was manufactured in Syncor, China. Each dog served as its own control, and was scanned by 99mTc-MIBI myocardial imaging and chocardiography at 48-72 hours before ligation. The mean time of the first acquisition was 21.87 ± 11.03 (14-48) minutes post-operatively in GA, 57.63±22.83 (30-99) minutes for 99mTc-MIBI imaging in GB, 26.00±15.07 (12-50) minutes for echocardiography in GB. Acquisition techniques for Gated SPECT: ECG synchronized data collection: R wave trigger, 8 Frames/Cardiac cycle. Images were gathered by rotating the detectors 180 degrees at 6 degrees per frame. Each frame took 40 seconds. The dog position was supine. The images were acquired and recorded for 6 hours following the LAD coronary artery ligation. After 6 hours

  7. Cell Wall Composition, Biosynthesis and Remodeling during Pollen Tube Growth

    Directory of Open Access Journals (Sweden)

    Jean-Claude Mollet

    2013-03-01

    Full Text Available The pollen tube is a fast tip-growing cell carrying the two sperm cells to the ovule allowing the double fertilization process and seed setting. To succeed in this process, the spatial and temporal controls of pollen tube growth within the female organ are critical. It requires a massive cell wall deposition to promote fast pollen tube elongation and a tight control of the cell wall remodeling to modify the mechanical properties. In addition, during its journey, the pollen tube interacts with the pistil, which plays key roles in pollen tube nutrition, guidance and in the rejection of the self-incompatible pollen. This review focuses on our current knowledge in the biochemistry and localization of the main cell wall polymers including pectin, hemicellulose, cellulose and callose from several pollen tube species. Moreover, based on transcriptomic data and functional genomic studies, the possible enzymes involved in the cell wall remodeling during pollen tube growth and their impact on the cell wall mechanics are also described. Finally, mutant analyses have permitted to gain insight in the function of several genes involved in the pollen tube cell wall biosynthesis and their roles in pollen tube growth are further discussed.

  8. Epigenetic regulation and chromatin remodeling in learning and memory.

    Science.gov (United States)

    Kim, Somi; Kaang, Bong-Kiun

    2017-01-13

    Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.

  9. Remodeling in the ischemic heart: the stepwise progression for heart

    Directory of Open Access Journals (Sweden)

    J.G. Mill

    2011-09-01

    Full Text Available Abstract Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI has decreased in the last decades. However, the incidence of heart failure (HF in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

  10. Prolactin promotes breast cancer cell migration through actin cytoskeleton remodeling

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    Priscilla Ludovico da Silva

    2015-12-01

    Full Text Available The role of prolactin on breast cancer development and progression is debated. Breast cancer progression largely depends on cell movement and on the ability to remodel the actin cytoskeleton. In this process, actin-binding proteins are requested to achieve fibrillar actin de-polymerization and relocation at the cell membrane. Kinases such as focal adhesion kinase (FAK are later required to form actin/vinculin-enriched structures called focal adhesion complexes, which mediate firm adhesion to the extracellular matrix. These controllers are regulated by c-Src, which forms multiprotein signaling complexes with membrane receptors and is regulated by a number of hormones, including prolactin. We here show that breast cancer cells exposed to prolactin display an elevated c-Src expression and phosphorylation. In parallel, increased moesin and FAK expression and phosphorylation are found. These molecular changes are associated to relocation to the plasma membrane of cytoskeletal actin fibers and to increased horizontal cell movement. In conclusion, prolactin regulates actin remodeling and enhances breast cancer cell movement. This finding broadens the understanding of prolactin actions on breast cancer cells, highlighting new pathways that may be relevant to on breast cancer progression.

  11. Mechanisms of bone remodeling: implications for clinical practice.

    Science.gov (United States)

    Kenny, Anne M; Raisz, Lawrence G

    2002-01-01

    The adult skeleton undergoes continuous remodeling. The remodeling cycle involves the interaction of cells of osteoblastic and osteoclastic lineage and is regulated by both systemic hormones and local factors. In addition to the systemic calcium-regulating hormones, parathyroid hormone, 1,25-dihydroxy vitamin D and calcitonin, sex hormones play an important role. Estrogen has been identified as the major inhibitor of bone resorption in both men and women. Androgen is important not only as a source of estrogen, through the action of aromatase, but also for its direct effect in stimulating bone formation. The effects of sex hormones may be mediated by their ability to alter the secretion of local cytokines, prostaglandins and growth factors. Sex hormone action is also modulated by the level of sex hormone-binding globulin in the circulation. A more precise analysis of these effects has been made possible by the development of new methods of measuring not only bone mineral density, but also relative rates of bone formation and resorption using biochemical markers. These new approaches have allowed us to define more precisely the specific roles of androgens, estrogens and other regulatory hormones in human skeletal physiology and pathophysiology.

  12. EFFECT OF INFLIXIMAB ON PARAMETERS OF REMODELING OF ARTERIAL BLOODSTREAM, RANKL AND OSTEOPROTEGERIN LEVELS IN PATIENTS WITH RHEUMATOID ARTHRITIS

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    Larisa Aleksandrovna Knyazeva

    2013-01-01

    Full Text Available Objective. To study the effect of infliximab (INF on serum levels of RANKL and osteoprotegerin (OPG, as well as on structural and functional properties of the vascular wall in patients with rheumatoid arthritis (RA.Material and Methods. A total of 79 RA patients who corresponded to the classification criteria ACR (1987 or ACR/EULAR (2010 and were seronegative for IgM rheumatoid factor (RF were examined. The mean age of patients was 43.6±8.5 years. The serum levels of OPG and RANKL were determined by ELISA (Biomedica, Austria; the common carotid arteries (CCAs were visualized using an Acuson X/10 ultrasonic complex equipped with a 7 MHz linear sensor in the β-mode prior to therapy and after 12-month therapy with INF.Results and Discussion. An increased OPG level was observed mostly in patients with RA duration up to 1 year; an increase in RANKL level was pronounced stronger in patients with PA duration over 2 years. The disturbance of structural and functional properties of the arterial bloodstream was revealed, manifesting itself as an increase in the intimamedia complex thickness, diameter and rigidity index of CCA that were stronger pronounced in patients with late onset RA. A correlation analysis showed the presence of reliable relationship between the RANKL and OPG levels and CCA remodeling parameters. INF therapy showed high clinical effectiveness and correction effect on the RANKL/OPG system. In addition, it was accompanied by a reduction of signs of CCA remodeling, which was stronger pronounced in patients with early RA.Conclusion. The results prove the reasonability of using INF at early stages of RA in order to optimize the therapy and achieve more efficient control of cardiovascular complications.

  13. Dual growth factor delivery from biofunctionalized allografts: Sequential VEGF and BMP-2 release to stimulate allograft remodeling.

    Science.gov (United States)

    Sharmin, Farzana; McDermott, Casey; Lieberman, Jay; Sanjay, Archana; Khan, Yusuf

    2017-05-01

    Autografts have been shown to stimulate osteogenesis, osteoclastogenesis, and angiogenesis, and subsequent rapid graft incorporation. Large structural allografts, however, suffer from limited new bone formation and remodeling, both of which are directly associated with clinical failure due to non-unions, late graft fractures, and infections, making it a priority to improve large structural allograft healing. We have previously shown the osteogenic ability of a polymer-coated allograft that delivers bone morphogenetic protein-2 both in vitro and in vivo through both burst release and sustained release kinetics. In this study, we have demonstrated largely sequential delivery of bone morphogenetic protein-2 and vascular endothelial growth factor from the same coated allograft. Release data showed that loading both growth factors onto a polymeric coating with two different techniques resulted in short-term (95% release within 2 weeks) and long-term (95% release within 5 weeks) delivery kinetics. We have also demonstrated how released VEGF, traditionally associated with angiogenesis, can also provide a stimulus for allograft remodeling via resorption. Bone marrow derived mononuclear cells were co-cultured with VEGF released from the coated allograft and showed a statistically significant (p exposed to VEGF released from the allografts over controls (p < 0.05). These results indicate that by using different loading protocols temporal control can be achieved when delivering multiple growth factors from a polymer-coated allograft. Further, released VEGF can also stimulate osteoclastogenesis that may enhance allograft incorporation, and thus mitigate long-term clinical complications. © 2017 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1086-1095, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  14. Temporal and Spatial Expression of Transforming Growth Factor-β after Airway Remodeling to Tobacco Smoke in Rats

    Science.gov (United States)

    Hoang, Laura L.; Nguyen, Yen P.; Aspeé, Rayza; Bolton, Sarah J.; Shen, Yi-hsin; Wang, Lei; Kenyon, Nicholas J.; Smiley-Jewell, Suzette

    2016-01-01

    Airway remodeling is strongly correlated with the progression of chronic obstructive pulmonary disease (COPD). In this study, our goal was to characterize progressive structural changes in site-specific airways, along with the temporal and spatial expression of transforming growth factor (TGF)-β in the lungs of male spontaneously hypertensive rats exposed to tobacco smoke (TS). Our studies demonstrated that TS-induced changes of the airways is dependent on airway generation and exposure duration for proximal, midlevel, and distal airways. Stratified squamous epithelial cell metaplasia was evident in the most proximal airways after 4 and 12 weeks but with minimal levels of TGF-β–positive epithelial cells after only 4 weeks of exposure. In contrast, epithelial cells in midlevel and distal airways were strongly TGF-β positive at both 4 and 12 weeks of TS exposure. Airway smooth muscle volume increased significantly at 4 and 12 weeks in midlevel airways. Immunohistochemistry of TGF-β was also found to be significantly increased at 4 and 12 weeks in lymphoid tissues and alveolar macrophages. ELISA of whole-lung homogenate demonstrated that TGF-β2 was increased after 4 and 12 weeks of TS exposure, whereas TGF-β1 was decreased at 12 weeks of TS exposure. Airway levels of messenger RNA for TGF-β2, as well as platelet-derived growth factor-A, granulocyte-macrophage colony–stimulating factor, and vascular endothelial growth factor-α, growth factors regulated by TGF-β, were significantly decreased in animals after 12 weeks of TS exposure. Our data indicate that TS increases TGF-β in epithelial and inflammatory cells in connection with airway remodeling, although the specific role of each TGF-β isoform remains to be defined in TS-induced airway injury and disease. PMID:26637070

  15. Vascularized osseous graft for scaphoid

    International Nuclear Information System (INIS)

    Mendez Daza, Carlos Hernan; Mathoulin, Cristophe

    2004-01-01

    The most commonly used technique for treatment of pseudo-arthrosis of the scaphoid is osteo-synthesis with Kirschnet wires and cortical sponge grafts. Results reported by different teams using this procedure show no more than 90% osseous consolidation, especially in cases where vascularisation of the proximal fragment of the scaphoid is compromised. Here we present a series of ten cases of pseudo-arthrosis of the scaphoid, treated using a new surgical technique involving a vascularized osseous graft of the distal radius. Using this procedure we obtained 100% consolidation, with no complications either during the procedure or immediately post-operatively. Patients returned to work in week 15 on average. In 4 cases we observed discomfort in the area of the scar, which was successfully treated using local cortisone injection. The results obtained are very similar to those seen in the literature on the different techniques for vascularized osseous grafts for pseudo-arthrosis of the scaphoid

  16. [Menopause: Hypertension and vascular disease].

    Science.gov (United States)

    Zilberman, J M

    Hypertension is the main cardiovascular risk factor affecting 25% of women. Hormone changes and hypertension after menopause may lead to higher target organ damage and cardiovascular disease such as increased arterial stiffness, coronary diseases, chronic heart failure and stroke. The physiopathological mechanisms involved in the development of hypertension and cardiovascular diseases in menopausal women are controversial. There are pharmacokinetic and pharmacodynamic differences in both sexes, the women have more coughing when using the converting-enzyme inhibitors, more cramps when using thiazide diuretics and more oedema in the inferior limbs when using calcium antagonists. The aim of this review is to analyse possible physiopathological mechanisms involved in hypertension after menopause and to gain a better understanding of the biological effects mediated by vascular ageing in women when the level of oestrogen protective effect decreases over the vascular system. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Vascular diagnostics for Raynaud's phenomenon

    Directory of Open Access Journals (Sweden)

    Dinsdale G

    2014-10-01

    Full Text Available Graham Dinsdale, Ariane L Herrick Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK Abstract: Raynaud's phenomenon (RP is common, and in most patients is primary (idiopathic when due to reversible vasospasm and does not progress to irreversible tissue injury. However, in those patients for whom RP is secondary to an underlying disease (eg, systemic sclerosis or atherosclerosis, progression to digital ulceration or critical ischemia can occur. Therefore, the key question for the clinician is “Why does this patient have RP?” Vascular diagnostics play a key role in answering this. In this review, we firstly discuss the different vascular investigations relevant to clinical practice: nail fold capillaroscopy (including the different methodologies for examining the nail fold capillaries, and the role of capillaroscopy in helping to differentiate between primary and systemic sclerosis-related RP, thermography (available in specialist centers, and evaluation of large vessel disease (for example, due to atherosclerosis. We then discuss research tools, mainly laser Doppler methods, including laser Doppler imaging and laser speckle contrast imaging. These are commercially available as complete imaging systems and are (relatively easy to use. The main current goal in vascular imaging research is to validate these novel state-of-the-art techniques as outcome measures of digital vascular disease, and then apply them in early and later phase studies of new treatment approaches, thus facilitating drug development programs. Keywords: Raynaud's phenomenon, systemic sclerosis, nail fold capillaroscopy, thermography, laser Doppler, angiography

  18. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

    Science.gov (United States)

    Langdahl, Bente; Ferrari, Serge; Dempster, David W

    2016-12-01

    The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that

  19. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

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    Fadel Elie

    2011-09-01

    Full Text Available Abstract Background Involvement of inflammation in pulmonary hypertension (PH has previously been demonstrated and recently, immune-modulating dendritic cells (DCs infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS, as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT, monocrotaline-exposure/pneumonectomy (MCT/PE. Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature

  20. Short-term adaptation and chronic cardiac remodelling to high altitude in lowlander natives and Himalayan Sherpa.

    Science.gov (United States)

    Stembridge, Mike; Ainslie, Philip N; Shave, Rob

    2015-11-01

    What is the topic of this review? At high altitude, the cardiovascular system must adapt in order to meet the metabolic demand for oxygen. This review summarizes recent findings relating to short-term and life-long cardiac adaptation to high altitude in the context of exercise capacity. What advances does it highlight? Both Sherpa and lowlanders exhibit smaller left ventricular volumes at high altitude; however, myocardial relaxation, as evidenced by diastolic untwist, is reduced only in Sherpa, indicating that short-term hypoxia does not impair diastolic relaxation. Potential remodelling of systolic function, as evidenced by lower left ventricular systolic twist in Sherpa, may facilitate the requisite sea-level mechanical reserve required during exercise, although this remains to be confirmed. Both short-term and life-long high-altitude exposure challenge the cardiovascular system to meet the metabolic demand for O2 in a hypoxic environment. As the demand for O2 delivery increases during exercise, the circulatory component of oxygen transport is placed under additional stress. Acute adaptation and chronic remodelling of cardiac structure and function may occur to facilitate O2 delivery in lowlanders during sojourn to high altitude and in permanent highland residents. However, our understanding of cardiac structural and functional adaption in Sherpa remains confined to a higher maximal heart rate, lower pulmonary vascular resistance and no differences in resting cardiac output. Ventricular form and function are intrinsically linked through the left ventricular (LV) mechanics that facilitate efficient ejection, minimize myofibre stress during contraction and aid diastolic recoil. Recent examination of LV mechanics has allowed detailed insight into fundamental cardiac adaptation in high-altitude Sherpa. In this symposium report, we review recent advances in our understanding of LV function in both lowlanders and Sherpa at rest and discuss the potential consequences

  1. Study on post occupancy evaluation after remodeling in accordance with the `green remodeling certification standards of existing non-residential buildings'- Focusing on the case of H building

    Science.gov (United States)

    Cho, Kyungjoo; Cho, Dongwoo; Yoon, Yosun

    2018-06-01

    South Korea has adopted the Paris Convention and promised to reduce greenhouse gas emissions by 37% from business-as-usual (BAU) levels in the `First Basic Plan to Respond to Climate Change'. The reduction goal of greenhouse gas cannot be achieved considering only new buildings; the analysis results shows that the reduction of greenhouse gas emissions from existing buildings is essential. `The Green Remodeling Certification Standards', established in South Korea in 2016, is in line with the above plan. The post-occupancy evaluation (POE) of remodeled buildings after applying the `Green Remodeling Certification Standards of Existing Buildings' must be studied for expansion of this scheme. The study results are expected to be used as foundational data for the promotion of remodeling existing buildings.

  2. Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

    NARCIS (Netherlands)

    Januskevicius, Andrius; Gosens, Reinoud; Sakalauskas, Raimundas; Vaitkiene, Simona; Janulaityte, Ieva; Halayko, Andrew J; Hoppenot, Deimante; Malakauskas, Kestutis

    2017-01-01

    Background: Airway smooth muscle (ASM) remodeling is an important component of the structural changes to airways seen in asthma. Eosinophils are the prominent inflammatory cells in asthma, and there is some evidence that they contribute to ASM remodeling via released mediators and direct contact

  3. Predictors and prognostic value of left atrial remodelling after acute myocardial infarction

    DEFF Research Database (Denmark)

    Kyhl, Kasper; Vejlstrup, Niels; Lønborg, Jacob

    2015-01-01

    PURPOSE: Left atrial (LA) volume is a strong prognostic predictor in patients following ST-segment elevation myocardial infarction (STEMI). However, the change in LA volume over time (LA remodelling) following STEMI has been scarcely studied. We sought to identify predictors for LA remodelling an...

  4. Airway Inflammation and Remodeling in Two Mouse Models of Asthma : Comparison of Males and Females

    NARCIS (Netherlands)

    Blacquiere, M. J.; Hylkema, M. N.; Postma, D. S.; Geerlings, M.; Timens, W.; Melgert, B. N.

    2010-01-01

    Background: Asthma and especially severe asthma affect women more frequently than men. Since asthma severity correlates with remodeling changes in the lung, a female propensity to remodeling could be expected. We studied whether our previous observation that female mice have more pronounced airway

  5. Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.

    Directory of Open Access Journals (Sweden)

    Qian Yin

    Full Text Available β-adrenergic receptors (β-ARs play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO at the dose of 0.25 mg·kg(-1·d(-1 for 7 days. We found that the expression of β1- and β2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB is a well-known transcription factor of β-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR, a RNA binding protein, which binds to the 3'-untranslated region of the β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling.

  6. Bone remodelling: its local regulation and the emergence of bone fragility.

    Science.gov (United States)

    Martin, T John; Seeman, Ego

    2008-10-01

    Bone modelling prevents the occurrence of damage by adapting bone structure - and hence bone strength - to its loading circumstances. Bone remodelling removes damage, when it inevitably occurs, in order to maintain bone strength. This cellular machinery is successful during growth, but fails during advancing age because of the development of a negative balance between the volumes of bone resorbed and formed during remodelling by the basic multicellular unit (BMU), high rates of remodelling during midlife in women and late in life in both sexes, and a decline in periosteal bone formation. together resulting in bone loss and structural decay each time a remodelling event occurs. The two steps in remodelling - resorption of a volume of bone by osteoclasts and formation of a comparable volume by osteoblasts - are sequential, but the regulatory events leading to these two fully differentiated functions are not. Reparative remodelling is initiated by damage producing osteocyte apoptosis, which signals the location of damage via the osteocyte canalicular system to endosteal lining cells which forms the canopy of a bone-remodelling compartment (BRC). Within the BRC, local recruitment of osteoblast precursors from the lining cells, the marrow and circulation, direct contact with osteoclast precursors, osteoclastogenesis and molecular cross-talk between precursors, mature cells, cells of the immune system, and products of the resorbed matrix, titrate the birth, work and lifespan of the cells of this multicellular remodelling machinery to either remove or form a net volume of bone appropriate to the mechanical requirements.

  7. Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice

    NARCIS (Netherlands)

    Palmen, M.; Daemen, M. J.; Bronsaer, R.; Dassen, W. R.; Zandbergen, H. R.; Kockx, M.; Smits, J. F.; van der Zee, R.; Doevendans, P. A.

    2001-01-01

    To obtain more insight in the role of IGF-1 in cardiac remodeling and function after experimental myocardial infarction. We hypothesized that cardiac remodeling is altered in IGF-1 deficient mice, which may affect cardiac function. A myocardial infarction was induced by surgical coronary artery

  8. Diffusion tensor imaging of left ventricular remodeling in response to myocardial infarction in the mouse

    NARCIS (Netherlands)

    Strijkers, Gustav J.; Bouts, Annemiek; Blankesteijn, W. Matthijs; Peeters, Tim H. J. M.; Vilanova, Anna; van Prooijen, Mischa C.; Sanders, Honorius M. H. F.; Heijman, Edwin; Nicolay, Klaas

    2009-01-01

    The cardiac muscle architecture lies at the basis of the mechanical and electrical properties of the heart, and dynamic alterations in fiber structure are known to be of prime importance in healing and remodeling after myocardial infarction. In this study, left ventricular remodeling was

  9. Phosphorylation of linker histones regulates ATP-dependent chromatin remodeling enzymes.

    NARCIS (Netherlands)

    Horn, P.J.; Carruthers, L.M.; Logie, C.; Hill, D.A.; Solomon, M.J.; Wade, P.A.; Imbalzano, A.N.; Hansen, J.; Peterson, C.L.

    2002-01-01

    Members of the ATP-dependent family of chromatin remodeling enzymes play key roles in the regulation of transcription, development, DNA repair and cell cycle control. We find that the remodeling activities of the ySWI/SNF, hSWI/SNF, xMi-2 and xACF complexes are nearly abolished by incorporation of

  10. Possible role of differential growth in airway wall remodeling in asthma

    KAUST Repository

    Moulton, D. E.; Goriely, A.

    2011-01-01

    Possible role of differential growth in airway wall remodeling in asthma. J Appl Physiol 110: 1003-1012, 2011. First published January 20, 2011; doi:10.1152/japplphysiol.00991.2010.- Airway remodeling in patients with chronic asthma is characterized

  11. YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration

    DEFF Research Database (Denmark)

    Yui, Shiro; Azzolin, Luca; Maimets, Martti

    2018-01-01

    by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous...

  12. [Bone Cell Biology Assessed by Microscopic Approach. Bone histomorphometry of remodeling, modeling and minimodeling].

    Science.gov (United States)

    Yamamoto, Noriaki; Shimakura, Taketoshi; Takahashi, Hideaki

    2015-10-01

    Bone histomorphometry is defined as a quantitative evaluation of bone remodeling. In bone remodeling, bone resorption and bone formation are coupled with scalloped cement lines. Another mechanism of bone formation is minimodeling which bone formation and resorption are independent. The finding of minimodeling appeared in special condition with metabolic bone disease or anabolic agents. We need further study for minimodeling feature and mechanism.

  13. Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK.

    Science.gov (United States)

    Martínez-Revelles, Sonia; García-Redondo, Ana B; Avendaño, María S; Varona, Saray; Palao, Teresa; Orriols, Mar; Roque, Fernanda R; Fortuño, Ana; Touyz, Rhian M; Martínez-González, Jose; Salaices, Mercedes; Rodríguez, Cristina; Briones, Ana M

    2017-09-01

    Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H 2 O 2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H 2 O 2 and O 2 .- levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H 2 O 2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27

  14. ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Qing Lu

    Full Text Available Estrogen promotes the proliferation and migration of vascular endothelial cells (ECs, which likely underlies its ability to accelerate re-endothelialization and reduce adverse remodeling after vascular injury. In previous studies, we have shown that the protective effects of E2 (the active endogenous form of estrogen in vascular injury require the estrogen receptor alpha (ERα. ERα transduces the effects of estrogen via a classical DNA binding, "genomic" signaling pathway and via a more recently-described "rapid" signaling pathway that is mediated by a subset of ERα localized to the cell membrane. However, which of these pathways mediates the effects of estrogen on endothelial cells is poorly understood. Here we identify a triple point mutant version of ERα (KRR ERα that is specifically defective in rapid signaling, but is competent to regulate transcription through the "genomic" pathway. We find that in ECs expressing wild type ERα, E2 regulates many genes involved in cell migration and proliferation, promotes EC migration and proliferation, and also blocks the adhesion of monocytes to ECs. ECs expressing KRR mutant ERα, however, lack all of these responses. These observations establish KRR ERα as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ERα rapid signaling. Further, they support that rapid signaling through ERα is essential for many of the transcriptional and physiological responses of ECs to E2, and that ERα rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen.

  15. Right ventricular remodelling after transcatheter pulmonary valve implantation.

    Science.gov (United States)

    Pagourelias, Efstathios D; Daraban, Ana M; Mada, Razvan O; Duchenne, Jürgen; Mirea, Oana; Cools, Bjorn; Heying, Ruth; Boshoff, Derize; Bogaert, Jan; Budts, Werner; Gewillig, Marc; Voigt, Jens-Uwe

    2017-09-01

    To define the optimal timing for percutaneous pulmonary valve implantation (PPVI) in patients with severe pulmonary regurgitation (PR) after Fallot's Tetralogy (ToF) correction. PPVI among the aforementioned patients is mainly driven by symptoms or by severe right ventricular (RV) dilatation/dysfunction. The optimal timing for PPVI is still disputed. Twenty patients [age 13.9 ± 9.2 years, (range 4.3-44.9), male 70%] with severe PR (≥3 grade) secondary to previous correction of ToF, underwent Melody valve (Medtronic, Minneapolis, MN) implantation, after a pre-stent placement. Full echocardiographic assessment (traditional and deformation analysis) and cardiovascular magnetic resonance evaluation were performed before and at 3 months after the intervention. 'Favorable remodelling' was considered the upper quartile of RV size decrease (>20% in 3 months). After PPVI, indexed RV effective stroke volume increased from 38.4 ± 9.5 to 51.4 ± 10.7 mL/m 2 , (P = 0.005), while RV end-diastolic volume and strain indices decreased (123.1 ± 24.1-101.5 ± 18.3 mL/m 2 , P = 0.005 and -23.5 ± 2.5 to -21 ± 2.5%, P = 0.002, respectively). After inserting pre-PPVI clinical, RV volumetric and deformation parameters in a multiple regression model, only time after last surgical correction causing PR remained as significant regressor of RV remodelling [R 2  = 0.60, beta = 0.387, 95%CI(0.07-0.7), P = 0.019]. Volume reduction and functional improvement were more pronounced in patients treated with PPVI earlier than 7 years after last RV outflow tract (RVOT) correction, reaching close-to-normal values. Early PPVI (<7 years after last RVOT operation) is associated with a more favorable RV reverse remodelling toward normal range and should be considered, before symptoms or RV damage become apparent. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  16. Growth and remodeling play opposing roles during postnatal human heart valve development.

    Science.gov (United States)

    Oomen, Pim J A; Holland, Maria A; Bouten, Carlijn V C; Kuhl, Ellen; Loerakker, Sandra

    2018-01-19

    Tissue growth and remodeling are known to govern mechanical homeostasis in biological tissue, but their relative contributions to homeostasis remain unclear. Here, we use mechanical models, fueled by experimental findings, to demonstrate that growth and remodeling have different effects on heart valve stretch homeostasis during physiological postnatal development. Two developmental stages were considered: early-stage (from infant to adolescent) and late-stage (from adolescent to adult) development. Our models indicated that growth and remodeling play opposing roles in preserving tissue stretch and with time. During early-stage development, excessive tissue stretch was decreased by tissue growth and increased by remodeling. In contrast, during late-stage development tissue stretch was decreased by remodeling and increased by growth. Our findings contribute to an improved understanding of native heart valve adaptation throughout life, and are highly relevant for the development of tissue-engineered heart valves.

  17. Can experimental data in humans verify the finite element-based bone remodeling algorithm?

    DEFF Research Database (Denmark)

    Wong, C.; Gehrchen, P.M.; Kiaer, T.

    2008-01-01

    STUDY DESIGN: A finite element analysis-based bone remodeling study in human was conducted in the lumbar spine operated on with pedicle screws. Bone remodeling results were compared to prospective experimental bone mineral content data of patients operated on with pedicle screws. OBJECTIVE......: The validity of 2 bone remodeling algorithms was evaluated by comparing against prospective bone mineral content measurements. Also, the potential stress shielding effect was examined using the 2 bone remodeling algorithms and the experimental bone mineral data. SUMMARY OF BACKGROUND DATA: In previous studies...... operated on with pedicle screws between L4 and L5. The stress shielding effect was also examined. The bone remodeling results were compared with prospective bone mineral content measurements of 4 patients. They were measured after surgery, 3-, 6- and 12-months postoperatively. RESULTS: After 1 year...

  18. Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery

    NARCIS (Netherlands)

    Pasterkamp, G.; Schoneveld, A. H.; Hijnen, D. J.; de Kleijn, D. P.; Teepen, H.; van der Wal, A. C.; Borst, C.

    2000-01-01

    Atherosclerotic luminal narrowing is determined by plaque mass and the mode of geometrical remodeling. Recently, we reported that the type of atherosclerotic remodeling is associated with the presence of histological markers for plaque vulnerability. Inflammation and matrix degrading proteases

  19. Electrical remodeling and atrial dilation during atrial tachycardia are influenced by ventricular rate : Role of developing tachycardiomyopathy

    NARCIS (Netherlands)

    Schoonderwoerd, BA; Van Gelder, IC; Van Veldhuisen, DJ; Tieleman, RG; Grandjean, JG; Bel, KJ; Allessie, MA; Crijns, HJGM

    2001-01-01

    Atrial Remodeling in Tachycardiomyopathy. Introduction: Atrial fibrillation (AF) and congestive heart failure (CHF) are two clinical entities that often coincide. Our aim was to establish the influence of concomitant high ventricular rate and consequent development of CHF on electrical remodeling

  20. Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

    NARCIS (Netherlands)

    Stankiewicz, P.; Khan, T.N.; Szafranski, P.; Slattery, L.; Streff, H.; Vetrini, F.; Bernstein, J.A.; Brown, C.W.; Rosenfeld, J.A.; Rednam, S.; Scollon, S.; Bergstrom, K.L.; Parsons, D.W.; Plon, S.E.; Vieira, M.W.; Quaio, C.; Baratela, W.A.R.; Guio, J.C.A.; Armstrong, R.; Mehta, S.G.; Rump, P.; Pfundt, R.P.; Lewandowski, R.; Fernandes, E.M.; Shinde, D.N.; Tang, S.; Hoyer, J.; Zweier, C.; Reis, A.; Bacino, C.A.; Xiao, R.; Breman, A.M.; Smith, J.L.; Katsanis, N.; Bostwick, B.; Popp, B.; Davis, E.E.; Yang, Y

    2017-01-01

    Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for

  1. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity

    International Nuclear Information System (INIS)

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro; Yasuda, Osamu; Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2011-01-01

    Highlights: → Telmisartan, an angiotensin receptor blocker, acts as a partial PPARγ agonist. → The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NFκB activation and TNF α. → PPARγ activity of telmisartan was involved in the normalization of vascular PPARγ downregulation in diabetic mice. → We provided the first evidence indicating that PPARγ activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor γ (PPARγ) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPARγ agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPARγ activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPARγ antagonist), and losartan with no PPARγ activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NFκB) activation and tumor necrosis factor α. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPARγ activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPARγ in db/db mice and this effect of telmisartan was cancelled by the coadministration

  2. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

    Energy Technology Data Exchange (ETDEWEB)

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto (Japan); Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Ogawa, Hisao [Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Kim-Mitsuyama, Shokei, E-mail: kimmitsu@gpo.kumamoto-u.ac.jp [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan)

    2011-07-08

    Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of

  3. Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

    Science.gov (United States)

    Neto-Neves, Evandro M; Brown, Mary B; Zaretskaia, Maria V; Rezania, Samin; Goodwill, Adam G; McCarthy, Brian P; Persohn, Scott A; Territo, Paul R; Kline, Jeffrey A

    2017-04-01

    Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  4. Adipose derived stromal vascular fraction improves early tendon healing: an experimental study in rabbits

    Directory of Open Access Journals (Sweden)

    Mehdi Behfar

    2011-11-01

    Full Text Available Tendon never restores the complete biological and mechanical properties after healing. Bone marrow and recently adipose tissue have been used as the sources of mesenchymal stem cells, which have been proven to enhance tendon healing. Stromal vascular fraction (SVF, derived from adipose tissue by an enzymatic digestion, represents an alternative source of multipotent cells, which undergo differentiation into multiple lineages to be used in regenerative medicine. In the present study, we investigated potentials of this source on tendon healing. Twenty rabbits were divided into control and treatment groups. Five rabbits were used as donors of adipose tissue. The injury model was unilateral complete transection through the middle one third of deep digital flexor tendon. Immediately after suture repair, either fresh stromal vascular fraction from enzymatic digestion of adipose tissue or placebo was intratendinously injected into the suture site in treatments and controls, respectively. Cast immobilization was continued for two weeks after surgery. Animals were sacrificed at the third week and tendons underwent histological, immunohistochemical, and mechanical evaluations. By histology, improved fibrillar organization and remodeling of neotendon were observed in treatment group. Immunohistochemistry revealed an insignificant increase in collagen type III and I expression in treatments over controls. Mechanical testing showed significant increase in maximum load and energy absorption in SVF treated tendons. The present study showed that intratendinous injection of uncultured adipose derived stromal vascular fraction improved structural and mechanical properties of repaired tendon and it could be an effective modality for treating tendon laceration.

  5. Effects of hydroxysafflor yellow A on proliferation and collagen synthesis of rat vascular adventitial fibroblasts induced by angiotensin II.

    Science.gov (United States)

    Yuan, Wendan; Yang, Dongxia; Sun, Xuhong; Liu, Wei; Wang, Liang; Li, Xiaoyan; Man, Xuejing; Fu, Qiang

    2014-01-01

    1) examine the effects of hydroxysafflor yellow A (HSYA) on the proliferation, collagen and cytokine synthesis of vascular adventitial fibroblasts as induced by angiotensin II (Ang II) in normal Sprague-Dawley (SD) rats in vitro, and 2) to assess the effects of HSYA on morphological changes and collagen accumulation of vascular adventitia in spontaneously hypertensive rats (SHR) in vivo. In vitro experiment, vascular adventitial fibroblasts from SD rats were isolated, cultured, and divided into control groups, model groups and HSYA groups. Cell morphology of adventitial fibroblasts was assessed using laser confocal microscopy, while cell proliferation with the MTT assay, and collagen synthesis was determined using hydroxyproline chromatometry. Immunocytochemistry and reverse transcription PCR were used for detecting the expression of TGF-β1, MMP-1, α-SMA and NF-κB in adventitial fibroblasts. In vivo experiment, vascular adventitia proliferation and collagen synthesis were analyzed using hematoxylin-eosin and Sirius staining. Our results showed that: 1) in vitro experiment of SD rats, HSYA inhibited proliferative activity and collagen synthesis of adventitial fibroblasts as induced by Ang II, and the inhibitory effects of HSYA on the increased expression of MMP-1, TGF-β1, α-SMA and NF-κB p65 as induced by Ang II were assessed, and 2) in vivo experiment of SHR, histological analysis displayed fewer pathological changes of vascular adventitia in HSYA treatment groups as compared with no HSYA treatment groups, and MMP-1, TGF-β1, α-SMA and NF-κB p65 expression significantly reduced after HSYA treatment (P adventitia components. This study provides experimental evidence demonstrating that HSYA has the capacity to decrease vascular adventitia proliferation and hyperplasia during vascular remodeling.

  6. Intestinal remodelling in mink fed with reduced protein content

    DEFF Research Database (Denmark)

    Chen, Pengmin; Zhao, Jingbo; Nielsen, Vivi Hunnicke

    2009-01-01

    Low protein intake occurs in humans in relation to diseases, starvation and post-operatively. Low-protein diets may affect the gastrointestinal structure and mechanical function. The aim was to study the passive biomechanical properties and tissue remodelling of the intestine in minks on reduced...... protein diets. Twenty-seven male minks were divided into three groups receiving different protein level in the diet for 6 weeks: High protein level (group H, 55% energy from protein), moderate protein level (group M, 30% energy from protein) and low protein level (group L, 15% energy from protein) (n=9...... groups. Feeding the low-protein diet shifted the stress-strain curves to the right for the circumferential direction, indicating the wall become softer in the circumferential direction. However, no significant difference was observed in the longitudinal direction for any of the intestinal segments...

  7. Brassinosteroid Mediated Cell Wall Remodeling in Grasses under Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Xiaolan Rao

    2017-05-01

    Full Text Available Unlike animals, plants, being sessile, cannot escape from exposure to severe abiotic stresses such as extreme temperature and water deficit. The dynamic structure of plant cell wall enables them to undergo compensatory changes, as well as maintain physical strength, with changing environments. Plant hormones known as brassinosteroids (BRs play a key role in determining cell wall expansion during stress responses. Cell wall deposition differs between grasses (Poaceae and dicots. Grass species include many important food, fiber, and biofuel crops. In this article, we focus on recent advances in BR-regulated cell wall biosynthesis and remodeling in response to stresses, comparing our understanding of the mechanisms in grass species with those in the more studied dicots. A more comprehensive understanding of BR-mediated changes in cell wall integrity in grass species will benefit the development of genetic tools to improve crop productivity, fiber quality and plant biomass recalcitrance.

  8. Meshless methods in biomechanics bone tissue remodelling analysis

    CERN Document Server

    Belinha, Jorge

    2014-01-01

    This book presents the complete formulation of a new advanced discretization meshless technique: the Natural Neighbour Radial Point Interpolation Method (NNRPIM). In addition, two of the most popular meshless methods, the EFGM and the RPIM, are fully presented. Being a truly meshless method, the major advantages of the NNRPIM over the FEM, and other meshless methods, are the remeshing flexibility and the higher accuracy of the obtained variable field. Using the natural neighbour concept, the NNRPIM permits to determine organically the influence-domain, resembling the cellulae natural behaviour. This innovation permits the analysis of convex boundaries and extremely irregular meshes, which is an advantage in the biomechanical analysis, with no extra computational effort associated.   This volume shows how to extend the NNRPIM to the bone tissue remodelling analysis, expecting to contribute with new numerical tools and strategies in order to permit a more efficient numerical biomechanical analysis.

  9. Remodelling of the microarchitecture of resistance arteries in cardiovascular diseases

    DEFF Research Database (Denmark)

    Bloksgaard, Maria; Brewer, Jonathan R.; Leurgans, Thomas

    Small resistance artery structure is an independent predictor of cardiovascular events in essential hypertension [1, 2] and diabetes (types I and II) [3, 4]. In particular, the media-to-lumen ratio (M:L) is predictive of cardiovascular events. The exact nature of this resistance artery remodeling...... in comparison to other well-studied microvascular beds (e.g. rat mesentery). In the future we aim to compare the microarchitecture of small resistance arteries from parietal pericardial biopsies between patients with and without (treated) hypertension, diabetes and/or ischemic heart disease. 1. Buus, N.H., et...... al., Small artery structure during antihypertensive therapy is an independent predictor of cardiovascular events in essential hypertension. J Hypertens, 2013. 31(4): p. 791-7. 2. Mathiassen, O.N., et al., Small artery structure is an independent predictor of cardiovascular events in essential...

  10. INO80 Chromatin Remodeling Coordinates Metabolic Homeostasis with Cell Division

    Directory of Open Access Journals (Sweden)

    Graeme J. Gowans

    2018-01-01

    Full Text Available Adaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the yeast metabolic cycle (YMC. Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here, we demonstrate that the INO80 chromatin-remodeling complex is required to coordinate respiration and cell division with periodic gene expression. Specifically, INO80 mutants have severe defects in oxygen consumption and promiscuous cell division that is no longer coupled with metabolic status. In mutant cells, chromatin accessibility of periodic genes, including TORC1-responsive genes, is relatively static, concomitant with severely attenuated gene expression. Collectively, these results reveal that the INO80 complex mediates metabolic signaling to chromatin to restrict proliferation to metabolically optimal states.

  11. Protein receptor-independent plasma membrane remodeling by HAMLET

    DEFF Research Database (Denmark)

    Nadeem, Aftab; Sanborn, Jeremy; Gettel, Douglas L.

    2015-01-01

    A central tenet of signal transduction in eukaryotic cells is that extra-cellular ligands activate specific cell surface receptors, which orchestrate downstream responses. This "protein-centric" view is increasingly challenged by evidence for the involvement of specialized membrane domains...... in signal transduction. Here, we propose that membrane perturbation may serve as an alternative mechanism to activate a conserved cell-death program in cancer cells. This view emerges from the extraordinary manner in which HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills a wide range...... of tumor cells in vitro and demonstrates therapeutic efficacy and selectivity in cancer models and clinical studies. We identify a "receptor independent" transformation of vesicular motifs in model membranes, which is paralleled by gross remodeling of tumor cell membranes. Furthermore, we find that HAMLET...

  12. Touch Receptors Undergo Rapid Remodeling in Healthy Skin

    Directory of Open Access Journals (Sweden)

    Kara L. Marshall

    2016-11-01

    Full Text Available Sensory tissues exposed to the environment, such as skin, olfactory epithelia, and taste buds, continuously renew; therefore, peripheral neurons must have mechanisms to maintain appropriate innervation patterns. Although somatosensory neurons regenerate after injury, little is known about how these neurons cope with normal target organ changes. To elucidate neuronal plasticity in healthy skin, we analyzed the structure of Merkel-cell afferents, which are gentle touch receptors, during skin remodeling that accompanies mouse hair-follicle regeneration. The number of Merkel cells is reduced by 90% and axonal arbors are simplified during active hair growth. These structures rebound within just days. Computational modeling predicts that Merkel-cell changes are probabilistic, but myelinated branch stability depends on Merkel-cell inputs. Electrophysiology and behavior demonstrate that tactile responsiveness is less reliable during active growth than in resting skin. These results reveal that somatosensory neurons display structural plasticity at the cost of impairment in the reliability of encoding gentle touch.

  13. Ghrelin improves vascular autophagy in rats with vascular calcification.

    Science.gov (United States)

    Xu, Mingming; Liu, Lin; Song, Chenfang; Chen, Wei; Gui, Shuyan

    2017-06-15

    This study aimed to investigate whether ghrelin ameliorated vascular calcification (VC) through improving autophagy. VC model was induced by nicotine plus vitamin D 3 in rats and β-glycerophosphate in vascular smooth muscle cell (VSMC). Calcium deposition was detected by von Kossa staining or alizarin red S staining. ALP activity was also detected. Western blot was used to assess the protein expression. Ghrelin treatment attenuated the elevation of calcium deposition and ALP activity in VC model both in vivo and in vitro. Interesting, the protein levels of autophagy markers, LC3 and beclin1 were significantly upregulated by ghrelin in VC model. An autophagy inhibitor, 3-methyladenine blocks the ameliorative effect of ghrelin on VC. Furthermore, protein expressions of phosphate-AMPK were increased by ghrelin treatment both in calcified aorta and VSMC. The effect of ghrelin on autophagy induction and VC attenuation was prevented by AMPK inhibitor, compound C. Our results suggested that ghrelin improved autophagy through AMPK activation, which was resulted in VC amelioration. These data maybe throw light on prevention and therapy of VC. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. A Collagen-based Scaffold Delivering Exogenous MicroRNA-29B to Modulate Extracellular Matrix Remodeling

    OpenAIRE

    Monaghan, Michael; Browne, Shane; Schenke-Layland, Katja; Pandit, Abhay

    2014-01-01

    Directing appropriate extracellular matrix remodeling is a key aim of regenerative medicine strategies. Thus, antifibrotic interfering RNA (RNAi) therapy with exogenous microRNA (miR)-29B was proposed as a method to modulate extracellular matrix remodeling following cutaneous injury. It was hypothesized that delivery of miR-29B from a collagen scaffold will efficiently modulate the extracellular matrix remodeling response and reduce maladaptive remodeling such as aggressive deposition of coll...

  15. The effect of radiation dose on mouse skeletal muscle remodeling

    International Nuclear Information System (INIS)

    Hardee, Justin P.; Puppa, Melissa J.; Fix, Dennis K.; Gao, Song; Hetzler, Kimbell L.; Bateman, Ted A.; Carson, James A.

    2014-01-01

    The purpose of this study was to determine the effect of two clinically relevant radiation doses on the susceptibility of mouse skeletal muscle to remodeling. Alterations in muscle morphology and regulatory signaling were examined in tibialis anterior and gastrocnemius muscles after radiation doses that differed in total biological effective dose (BED). Female C57BL/6 (8-wk) mice were randomly assigned to non-irradiated control, four fractionated doses of 4 Gy (4x4 Gy; BED 37 Gy), or a single 16 Gy dose (16 Gy; BED 100 Gy). Mice were sacrificed 2 weeks after the initial radiation exposure. The 16 Gy, but not 4x4 Gy, decreased total muscle protein and RNA content. Related to muscle regeneration, both 16 Gy and 4x4 Gy increased the incidence of central nuclei containing myofibers, but only 16 Gy increased the extracellular matrix volume. However, only 4x4 Gy increased muscle 4-hydroxynonenal expression. While both 16 Gy and 4x4 Gy decreased IIB myofiber mean cross-sectional area (CSA), only 16 Gy decreased IIA myofiber CSA. 16 Gy increased the incidence of small diameter IIA and IIB myofibers, while 4x4 Gy only increased the incidence of small diameter IIB myofibers. Both treatments decreased the frequency and CSA of low succinate dehydrogenase activity (SDH) fibers. Only 16 Gy increased the incidence of small diameter myofibers having high SDH activity. Neither treatment altered muscle signaling related to protein turnover or oxidative metabolism. Collectively, these results demonstrate that radiation dose differentially affects muscle remodeling, and these effects appear to be related to fiber type and oxidative metabolism

  16. Cells involved in extracellular matrix remodeling after acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Garcia, Larissa Ferraz [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Mataveli, Fábio D’Aguiar [Universidade Federal de São Paulo, São Paulo, SP (Brazil); Mader, Ana Maria Amaral Antônio; Theodoro, Thérèse Rachell [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Justo, Giselle Zenker; Pinhal, Maria Aparecida da Silva [Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2015-07-01

    Evaluate the effects of VEGF{sub 165} gene transfer in the process of remodeling of the extracellular matrix after an acute myocardial infarct. Wistar rats were submitted to myocardial infarction, after the ligation of the left descending artery, and the left ventricle ejection fraction was used to classify the infarcts into large and small. The animals were divided into groups of ten, according to the size of infarcted area (large or small), and received or not VEGF{sub 165} treatment. Evaluation of different markers was performed using immunohistochemistry and digital quantification. The primary antibodies used in the analysis were anti-fibronectin, anti-vimentin, anti-CD44, anti-E-cadherin, anti-CD24, anti-alpha-1-actin, and anti-PCNA. The results were expressed as mean and standard error, and analyzed by ANOVA, considering statistically significant if p≤0.05. There was a significant increase in the expression of undifferentiated cell markers, such as fibronectin (protein present in the extracellular matrix) and CD44 (glycoprotein present in the endothelial cells). However, there was decreased expression of vimentin and PCNA, indicating a possible decrease in the process of cell proliferation after treatment with VEGF{sub 165}. Markers of differentiated cells, E-cadherin (adhesion protein between myocardial cells), CD24 (protein present in the blood vessels), and alpha-1-actin (specific myocyte marker), showed higher expression in the groups submitted to gene therapy, compared to non-treated group. The value obtained by the relation between alpha-1-actin and vimentin was approximately three times higher in the groups treated with VEGF{sub 165}, suggesting greater tissue differentiation. The results demonstrated the important role of myocytes in the process of tissue remodeling, confirming that VEGF{sub 165} seems to provide a protective effect in the treatment of acute myocardial infarct.

  17. Oxidative stress in bone remodeling: role of antioxidants.

    Science.gov (United States)

    Domazetovic, Vladana; Marcucci, Gemma; Iantomasi, Teresa; Brandi, Maria Luisa; Vincenzini, Maria Teresa

    2017-01-01

    ROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss.

  18. Early remodeling of rat cardiac muscle induced by swimming training

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    Verzola R.M.M.

    2006-01-01

    Full Text Available The aim of the present investigation was to study the effect of acute swimming training with an anaerobic component on matrix metallopeptidase (MMP activity and myosin heavy chain gene expression in the rat myocardium. Animals (male Wistar rats, weighing approximately 180 g were trained for 6 h/day in 3 sessions of 2 h each for 1 to 5 consecutive days (N = 5 rats per group. Rats swam in basins 47 cm in diameter and 60 cm deep filled with water at 33 to 35ºC. After the training period a significant increase (P < 0.05 was observed in the heart weight normalized to body weight by about 22 and 35% in the groups that trained for 96 and 120 h, respectively. Blood lactate levels were significantly increased (P < 0.05 in all groups after all training sessions, confirming an anaerobic component. However, lactate levels decreased (P < 0.05 with days of training, suggesting that the animals became adapted to this protocol. Myosin heavy chain-ß gene expression, analyzed by real time PCR and normalized with GAPDH gene expression, showed a significant two-fold increase (P < 0.01 after 5 days of training. Zymography analysis of myocardium extracts indicated a single ~60-kDa activity band that was significantly increased (P < 0.05 after 72, 96, and 120 h, indicating an increased expression of MMP-2 and suggesting precocious remodeling. Furthermore, the presence of MMP-2 was confirmed by Western blot analysis, but not the presence of MMP-1 and MMP-3. Taken together, our results indicate that in these training conditions, the rat heart undergoes early biochemical and functional changes required for the adaptation to the new physiological condition by tissue remodeling.

  19. Cells involved in extracellular matrix remodeling after acute myocardial infarction

    International Nuclear Information System (INIS)

    Garcia, Larissa Ferraz; Mataveli, Fábio D’Aguiar; Mader, Ana Maria Amaral Antônio; Theodoro, Thérèse Rachell; Justo, Giselle Zenker; Pinhal, Maria Aparecida da Silva

    2015-01-01

    Evaluate the effects of VEGF_1_6_5 gene transfer in the process of remodeling of the extracellular matrix after an acute myocardial infarct. Wistar rats were submitted to myocardial infarction, after the ligation of the left descending artery, and the left ventricle ejection fraction was used to classify the infarcts into large and small. The animals were divided into groups of ten, according to the size of infarcted area (large or small), and received or not VEGF_1_6_5 treatment. Evaluation of different markers was performed using immunohistochemistry and digital quantification. The primary antibodies used in the analysis were anti-fibronectin, anti-vimentin, anti-CD44, anti-E-cadherin, anti-CD24, anti-alpha-1-actin, and anti-PCNA. The results were expressed as mean and standard error, and analyzed by ANOVA, considering statistically significant if p≤0.05. There was a significant increase in the expression of undifferentiated cell markers, such as fibronectin (protein present in the extracellular matrix) and CD44 (glycoprotein present in the endothelial cells). However, there was decreased expression of vimentin and PCNA, indicating a possible decrease in the process of cell proliferation after treatment with VEGF_1_6_5. Markers of differentiated cells, E-cadherin (adhesion protein between myocardial cells), CD24 (protein present in the blood vessels), and alpha-1-actin (specific myocyte marker), showed higher expression in the groups submitted to gene therapy, compared to non-treated group. The value obtained by the relation between alpha-1-actin and vimentin was approximately three times higher in the groups treated with VEGF_1_6_5, suggesting greater tissue differentiation. The results demonstrated the important role of myocytes in the process of tissue remodeling, confirming that VEGF_1_6_5 seems to provide a protective effect in the treatment of acute myocardial infarct

  20. Erythrocyte stiffness during morphological remodeling induced by carbon ion radiation.

    Directory of Open Access Journals (Sweden)

    Baoping Zhang

    Full Text Available The adverse effect induced by carbon ion radiation (CIR is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy or X-rays (2, 4, 6, and 12 Gy for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy. The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study

  1. Phase field approaches of bone remodeling based on TIP

    Science.gov (United States)

    Ganghoffer, Jean-François; Rahouadj, Rachid; Boisse, Julien; Forest, Samuel

    2016-01-01

    The process of bone remodeling includes a cycle of repair, renewal, and optimization. This adaptation process, in response to variations in external loads and chemical driving factors, involves three main types of bone cells: osteoclasts, which remove the old pre-existing bone; osteoblasts, which form the new bone in a second phase; osteocytes, which are sensing cells embedded into the bone matrix, trigger the aforementioned sequence of events. The remodeling process involves mineralization of the bone in the diffuse interface separating the marrow, which contains all specialized cells, from the newly formed bone. The main objective advocated in this contribution is the setting up of a modeling and simulation framework relying on the phase field method to capture the evolution of the diffuse interface between the new bone and the marrow at the scale of individual trabeculae. The phase field describes the degree of mineralization of this diffuse interface; it varies continuously between the lower value (no mineral) and unity (fully mineralized phase, e.g. new bone), allowing the consideration of a diffuse moving interface. The modeling framework is the theory of continuous media, for which field equations for the mechanical, chemical, and interfacial phenomena are written, based on the thermodynamics of irreversible processes. Additional models for the cellular activity are formulated to describe the coupling of the cell activity responsible for bone production/resorption to the kinetics of the internal variables. Kinetic equations for the internal variables are obtained from a pseudo-potential of dissipation. The combination of the balance equations for the microforce associated to the phase field and the kinetic equations lead to the Ginzburg-Landau equation satisfied by the phase field with a source term accounting for the dissipative microforce. Simulations illustrating the proposed framework are performed in a one-dimensional situation showing the evolution of

  2. Quantitative Estimates of Bio-Remodeling on Coastal Rock Surfaces

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    Marta Pappalardo

    2016-05-01

    Full Text Available Remodeling of rocky coasts and erosion rates have been widely studied in past years, but not all the involved processes acting over rocks surface have been quantitatively evaluated yet. The first goal of this paper is to revise the different methodologies employed in the quantification of the effect of biotic agents on rocks exposed to coastal morphologic agents, comparing their efficiency. Secondly, we focus on geological methods to assess and quantify bio-remodeling, presenting some case studies in an area of the Mediterranean Sea in which different geological methods, inspired from the revised literature, have been tested in order to provide a quantitative assessment of the effects some biological covers exert over rocky platforms in tidal and supra-tidal environments. In particular, different experimental designs based on Schmidt hammer test results have been applied in order to estimate rock hardness related to different orders of littoral platforms and the bio-erosive/bio-protective role of Chthamalus ssp. and Verrucariaadriatica. All data collected have been analyzed using statistical tests to evaluate the significance of the measures and methodologies. The effectiveness of this approach is analyzed, and its limits are highlighted. In order to overcome the latter, a strategy combining geological and experimental–computational approaches is proposed, potentially capable of revealing novel clues on bio-erosion dynamics. An experimental-computational proposal, to assess the indirect effects of the biofilm coverage of rocky shores, is presented in this paper, focusing on the shear forces exerted during hydration-dehydration cycles. The results of computational modeling can be compared to experimental evidence, from nanoscopic to macroscopic scales.

  3. Vascular dementia: Facts and controversies

    Directory of Open Access Journals (Sweden)

    Pavlović Aleksandra

    2013-01-01

    Full Text Available Vascular dementia (VaD is the second most frequent dementia after Alzheimer’s disease, and is diagnosed during lifetime in 20% of demented patients. Five­year survival rate in VaD is 39%, while it is estimated to be 75% in healthy persons of the same age. It is therefore important to make correct diagnosis of VaD early in the course of the disease. Risk factors for VaD are identical to stroke risk factors, and there are significant possibilities for the prevention of vascular cognitive decline. Cognitive decline develops acutely or step­by­step within three months after stroke, but more gradual progression of intellectual decline is also possible. Neurological examination can reveal pyramidal and extrapyramidal signs, pseudobulbar palsy, gait disturbance and urinary incontinence. Neuropsychological profile comprises the loss of cognitive set shifting, decline in word fluency, verbal learning difficulties, perseverations, difficulties in complex figure copying, and in patients with cortically located lesions also problems with speech and praxia. The basis of the diagnosis is, besides history, neurological examination and neuropsychological assessment, computed tomography and/ or magnetic resonance brain imaging. Vascular risk factors control is the most important measure in VaD prevention. Modern guidelines for the treatment of cognitive decline in VaD emphasize that donepezil can be useful in the improvement of cognitive status at the level of Class IIa recommendation at the level of evidence A, while memantine may be useful in patients with mixed VaD and Alzheimer’s disease dementia. [Projekat Ministarstva nauke Republike Srbije, br. 175022 i br. 175033

  4. 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

  5. Vascular comorbidities in multiple sclerosis

    DEFF Research Database (Denmark)

    Thormann, Anja; Magyari, Melinda; Koch-Henriksen, Nils

    2016-01-01

    To investigate the occurrence of vascular comorbidities before and after the clinical onset of multiple sclerosis. In this combined case-control and cohort study, all Danish born citizens with onset of multiple sclerosis 1980-2005 were identified from the Danish Multiple Sclerosis Registry...... and randomly matched with controls regarding year of birth, gender, and municipality on January 1st in the year of multiple sclerosis (MS) onset (index date). Individual-level information on comorbidities was obtained from several independent nationwide registries and linked to the study population by unique...

  6. Heritability of Retinal Vascular Fractals

    DEFF Research Database (Denmark)

    Vergmann, Anna Stage; Broe, Rebecca; Kessel, Line

    2017-01-01

    , the retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficients. Falconer's formula and quantitative genetic models were used to determine the genetic component of variation. Results: The mean...... fractal dimension did not differ statistically significantly between monozygotic and dizygotic twin pairs (1.505 vs. 1.495, P = 0.06), supporting that the study population was suitable for quantitative analysis of heritability. The intrapair correlation was markedly higher (0.505, P = 0...

  7. Composite vascular repair grafts via micro-imprinting and electrospinning

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yuanyuan, E-mail: yuanyuan-liu@shu.edu.cn; Hu, Qingxi, E-mail: huqingxi@shu.edu.cn [Rapid Manufacturing Engineering Center, Shanghai University, Shanghai 200444 (China); Shanghai Key Laboratory of Intelligent Manufacturing and Robotics, Shanghai 200072 (China); Xiang, Ke, E-mail: xiangke@shu.edu.cn; Chen, Haiping, E-mail: 519673062@qq.com; Li, Yu, E-mail: liyu@hpu.edu.cn [Rapid Manufacturing Engineering Center, Shanghai University, Shanghai 200444 (China)

    2015-04-15

    Composite vascular grafts formed by micro-imprinting and electrospinning exhibited improved mechanical properties relative to those formed by electrospinning alone. The three-layered composite grafts mimic the three-layered structure of natural blood vessels. The middle layer is made by micro-imprinting poly-p-dioxanone (PPDO), while the inner and outer layers are electrospun mixtures of chitosan and polyvinyl alcohol. The graft morphology is characterized with scanning electron microscopy. For constant graft thicknesses, the PPDO increases the mechanical strength. Cells cultivated on the vascular grafts adhere and proliferate better because of the natural, biological chitosan in the inner and outer layers. Overall, the composite scaffolds could be good candidates for blood vessel repair.

  8. Radiation dose to trabecular bone marrow stem cells from 3H, 14C and selected α-emitters incorporated in a bone remodeling compartment

    International Nuclear Information System (INIS)

    Nie Huiling; Richardson, Richard B

    2009-01-01

    A Monte Carlo simulation of repeated cubic units representing trabecular bone cavities in adult bone was employed to determine absorbed dose fractions evaluated for 3 H, 14 C and a set of α-emitters incorporated within a bone remodeling compartment (BRC). The BRC consists of a well-oxygenated vascular microenvironment located within a canopy of bone-lining cells. The International Commission on Radiological Protection (ICRP) considers that an important target for radiation-induced bone cancer is the endosteum marrow layer adjacent to bone surface where quiescent bone stem cells reside. It is proposed that the active stem cells and progenitor cells located above the BRC canopy, the 'BRC stem cell niche', is a more important radiation-induced cancer target volume. Simulation results from a static model, where no remodeling occurs, indicate that the mean dose from bone and bone surface to the 50 μm quiescent bone stem cell niche, the current ICRP target, was substantially lower (two to three times lower) than that to the narrower and hypoxic 10 μm endosteum for 3 H, 14 C and α-particles with energy range 0.5-10 MeV. The results from a dynamic model indicate that the temporal α-radiation dose to active stem/progenitor cells located in the BRC stem cell niche from the material incorporated in and buried by forming bone was 9- to 111-fold greater than the dose to the quiescent bone stem cell niche. This work indicates that the remodeling portion of the bone surface, rather than the quiescent (endosteal) surface, has the greatest risk of radiation-induced bone cancer, particularly from short-range radiation, due to the elevated dose and the radiosensitizing oxygen effect.

  9. EMMPRIN-mediated induction of uterine and vascular matrix metalloproteinases during pregnancy and in response to estrogen and progesterone.

    Science.gov (United States)

    Dang, Yiping; Li, Wei; Tran, Victoria; Khalil, Raouf A

    2013-09-15

    Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear. MMPs expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg) and late pregnant (late-Preg) rats. Western blots and gelatin zymography revealed increases in MMP-2 and -9 in uterus and aorta of late-Preg compared with virgin and mid-Preg rats. In contrast, MMP-2 and -9 were decreased in placenta of late-Preg versus mid-Preg rats. Extracellular MMP inducer (EMMPRIN) was increased in uterus and aorta of pregnant rats, but was less in placenta of late-Preg than mid-Preg rats. Prolonged treatment of uterus or aorta of virgin rats with 17β-estradiol and progesterone increased the amount of EMMPRIN, MMP-2 and -9, and the sex hormone-induced increases in MMPs were prevented by EMMPRIN neutralizing antibody. Immunohistochemistry revealed that MMP-2 and -9 and EMMPRIN increased in uterus and aorta of pregnant rats, but decreased in placenta of late-Preg versus mid-Preg rats. Thus pregnancy-associated upregulation of uterine MMPs is paralleled by increased vascular MMPs, and both are mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar role of MMPs in uterine and vascular tissue remodeling and function during pregnancy. The decreased MMPs and EMMPRIN in placenta of late-Preg rats suggests reduced role of MMPs in feto-placental circulation during late pregnancy. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Arborvitae (Thuja plicata essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts

    Directory of Open Access Journals (Sweden)

    Xuesheng Han

    2017-06-01

    Full Text Available Arborvitae (Thuja plicata essential oil (AEO is becoming increasingly popular in skincare, although its biological activity in human skin cells has not been investigated. Therefore, we sought to study AEO's effect on 17 important protein biomarkers that are closely related to inflammation and tissue remodeling by using a pre-inflamed human dermal fibroblast culture model. AEO significantly inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1, intracellular cell adhesion molecule 1 (ICAM-1, interferon gamma-induced protein 10 (IP-10, interferon-inducible T-cell chemoattractant (I-TAC, monokine induced by interferon gamma (MIG, and macrophage colony-stimulating factor (M-CSF. It also showed significant antiproliferative activity and robustly inhibited collagen-I, collagen-III, plasminogen activator inhibitor-1 (PAI-1, and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2. The inhibitory effect of AEO on increased production of these protein biomarkers suggests it has anti-inflammatory property. We then studied the effect of AEO on the genome-wide expression of 21,224 genes in the same cell culture. AEO significantly and diversely modulated global gene expression. Ingenuity pathway analysis (IPA showed that AEO robustly affected numerous critical genes and signaling pathways closely involved in inflammatory and tissue remodeling processes. The findings of this study provide the first evidence of the biological activity and beneficial action of AEO in human skin cells.

  11. Effect of antiprogesterone RU486 on VEGF expression and blood vessel remodeling on ovarian follicles before ovulation.

    Directory of Open Access Journals (Sweden)

    Annunziata Mauro

    Full Text Available BACKGROUND: The success of ovarian follicle growth and ovulation is strictly related to the development of an adequate blood vessel network required to sustain the proliferative and endocrine functions of the follicular cells. Even if the Vascular Endothelial Growth Factor (VEGF drives angiogenesis before ovulation, the local role exerted by Progesterone (P₄ remains to be clarified, in particular when its concentration rapidly increases before ovulation. AIM: This in vivo study was designed to clarify the effect promoted by a P₄ receptor antagonist, RU486, on VEGF expression and follicular angiogenesis before ovulation, in particular, during the transition from pre to periovulatory follicles induced by human Chorionic Gonadotropins (hCG administration. MATERIAL AND METHODS: Preovulatory follicle growth and ovulation were pharmacologically induced in prepubertal gilts by combining equine Chorionic Gonadotropins (eCG and hCG used in the presence or absence of RU486. The effects on VEGF expression were analyzed using biochemical and immunohistochemical studies, either on granulosa or on theca layers of follicles isolated few hours before ovulation. This angiogenic factor was also correlated to follicular morphology and to blood vessels architecture. RESULTS AND CONCLUSIONS: VEGF production, blood vessel network and follicle remodeling were impaired by RU486 treatment, even if the cause-effect correlation remains to be clarified. The P₄ antagonist strongly down-regulated theca VEGF expression, thus, preventing most of the angiogenic follicle response induced by hCG. RU486-treated follicles displayed a reduced vascular area, a lower rate of endothelial cell proliferation and a reduced recruitment of perivascular mural cells. These data provide important insights on the biological role of RU486 and, indirectly, on steroid hormones during periovulatory follicular phase. In addition, an in vivo model is proposed to evaluate how periovulatory

  12. CIRSE Vascular Closure Device Registry

    International Nuclear Information System (INIS)

    Reekers, Jim A.; Müller-Hülsbeck, Stefan; Libicher, Martin; Atar, Eli; Trentmann, Jens; Goffette, Pierre; Borggrefe, Jan; Zeleňák, Kamil; Hooijboer, Pieter; Belli, Anna-Maria

    2011-01-01

    Purpose: Vascular closure devices are routinely used after many vascular interventional radiology procedures. However, there have been no major multicenter studies to assess the safety and effectiveness of the routine use o