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Sample records for blood vascular endothelial

  1. Soluble vascular endothelial growth factor in various blood transfusion components

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Werther, K; Mynster, T;

    1999-01-01

    BACKGROUND: Blood transfusion may reduce survival after curative surgery for solid tumors. This may be related to extracellular content of cancer growth factors present in transfusion components. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis in solid tumors....... The potential content of VEGF in various blood components for transfusion was evaluated. STUDY DESIGN AND METHODS: Soluble VEGF (sVEGF, isotype 165) was determined by an enzyme-linked immunosorbent assay (EIA) in serum and plasma samples and in lysed cells from healthy volunteers. Subsequently, total content...... of platelet-derived soluble plasminogen activator inhibitor type 1 (sPAI-1) was determined by an EIA in the same samples. Finally, the extracellular accumulation of sVEGF was determined in nonfiltered WB and SAGM blood during storage for 35 days and in BCP pools during storage for 7 days. RESULTS...

  2. Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo.

    Science.gov (United States)

    Ashina, Kohei; Tsubosaka, Yoshiki; Nakamura, Tatsuro; Omori, Keisuke; Kobayashi, Koji; Hori, Masatoshi; Ozaki, Hiroshi; Murata, Takahisa

    2015-01-01

    Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

  3. Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis.

    Science.gov (United States)

    Ren, Younan; Tao, Shanjun; Zheng, Shuguo; Zhao, Mengqiu; Zhu, Yuanmei; Yang, Jieren; Wu, Yuanjie

    2016-11-15

    Vascular endothelial cell injury is an initial event in atherosclerosis. Salvianolic acid B (Sal B), a main bioactive component in the root of Salvia miltiorrhiza, has vascular protective effect in diabetes, but the underlying mechanisms remain unclear. The present study investigated the effect of Sal B on vascular endothelial function in diabetic rats with blood glucose fluctuations and the possible mechanisms implicated. The results showed that diabetic rats developed marked endothelial dysfunction as exhibited by impaired acetylcholine induced vasodilation. Supplementation with Sal B resulted in an evident improvement of endothelial function. Phosphorylation (Ser 1177) of endothelial nitric oxide synthase (eNOS) was significantly restored in Sal B treated diabetic rats, accompanied by an evident recovery of NO metabolites. Sal B effectively reduced vascular endothelial cell apoptosis, with Bcl-2 protein up-regulated and Bax protein down-regulated markedly. Treatment with Sal B led to an evident amelioration of oxidative stress in diabetic rats as manifested by enhanced antioxidant capacity and decreased contents of malondialdehyde in aortas. Protein levels of NOX2 and NOX4, two main isoforms of NADPH oxidase known as the major source of reactive oxygen species in the vasculature, were markedly decreased in Sal B treated groups. In addition, treatment with Sal B led to an evident decrease of serum lipids. Taken together, this study indicates that Sal B is capable of improving endothelial function in diabetic rats with blood glucose fluctuations, of which the underlying mechanisms might be related to suppression of endothelial cell apoptosis and stimulation of eNOS phosphorylation (Ser 1177).

  4. Differential Gene Expression of Primary Cultured Lymphatic and Blood Vascular Endothelial Cells

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    Gregory M. Nelson

    2007-12-01

    Full Text Available Blood vascular endothelial cells (BECs and the developmentally related lymphatic endothelial cells (LECs create complementary, yet distinct vascular networks. Each endothelial cell type interacts with flowing fluid and circulating cells, yet each vascular system has evolved specialized gene expression programs and thus both cell types display different phenotypes. BECs and LECs express distinct genes that are unique to their specific vascular microenvironment. Tumors also take advantage of the molecules that are expressed in these vascular systems to enhance their metastatic potential. We completed transcriptome analyses on primary cultured LECs and BECs, where each comparative set was isolated from the same individual. Differences were resolved in the expression of several major categories, such as cell adhesion molecules (CAMs, cytokines, cytokine receptors. We have identified new molecules that are associated with BECs (e.g., claudin-9, CXCL11, neurexin-1, neurexin-2, the neuronal growth factor regulator-1 and LECs (e.g., claudin-7, CD58, hyaluronan and proteoglycan link protein 1 (HAPLN1, the poliovirus receptor-related 3 molecule that may lead to novel therapeutic treatments for diseases of lymphatic or blood vessels, including metastasis of cancer to lymph nodes or distant organs.

  5. Soluble vascular endothelial growth factor in various blood transfusion components

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Werther, K; Mynster, T

    1999-01-01

    of sVEGF was determined in nonfiltered and prestorage white cell-reduced whole blood (WB), buffy coat-depleted saline-adenine-glucose-mannitol (SAGM) blood, platelet-rich plasma (PRP), and buffy coat-derived platelet (BCP) pools obtained from volunteer, healthy blood donors. As a control, total content....... The potential content of VEGF in various blood components for transfusion was evaluated. STUDY DESIGN AND METHODS: Soluble VEGF (sVEGF, isotype 165) was determined by an enzyme-linked immunosorbent assay (EIA) in serum and plasma samples and in lysed cells from healthy volunteers. Subsequently, total content......: In the healthy volunteers, median total sVEGF content was 97 (range, 20-303) pg per mL in serum and 19 (13-37) pg per mL in plasma (n = 12, p plasma, and 95 (78...

  6. Cord blood-circulating endothelial progenitors for treatment of vascular diseases.

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    Lavergne, M; Vanneaux, V; Delmau, C; Gluckman, E; Rodde-Astier, I; Larghero, J; Uzan, G

    2011-04-01

    Adult peripheral blood (PB) endothelial progenitor cells (EPC) are produced in the bone marrow and are able to integrate vascular structures in sites of neoangiogenesis. EPCs thus represent a potential therapeutic tool for ischaemic diseases. However, use of autologous EPCs in cell therapy is limited by their rarity in adult PB. Cord blood (CB) contains more EPCs than PB, and they are functional after expansion. They form primary colonies that give rise to secondary colonies, each yielding more than 10(7) cells after few passages. The number of endothelial cells obtained from one unit of CB is compatible with potential clinical application. EPC colonies can be securely produced, expanded and cryopreserved in close culture devices and endothelial cells produced in these conditions are functional as shown in different in vitro and in vivo assays. As CB EPC-derived endothelial cells would be allogeneic to patients, it would be of interest to prepare them from ready-existing CB banks. We show that not all frozen CB units from a CB bank are able to generate EPC colonies in culture, and when they do so, number of colonies is lower than that obtained with fresh CB units. However, endothelial cells derived from frozen CB have the same phenotypical and functional properties than those derived from fresh CB. This indicates that CB cryopreservation should be improved to preserve integrity of stem cells other than haematopoietic ones. Feasibility of using CB for clinical applications will be validated in porcine models of ischaemia.

  7. Effect of mitiglinide combined laser photocoagulation on blood glucose, blood lipid and vascular endothelial function in diabetic retinopathy

    Institute of Scientific and Technical Information of China (English)

    Yun-Yan Fan; Gui-Jun Luo

    2016-01-01

    Objective:To observe the effect of mitiglinide combined laser photocoagulation on blood glucose, blood lipid and vascular endothelial function in diabetic retinopathy.Methods:A total of 106 patients with diabetic retinopathy treated in our hospital from January 2014 to January 2015 were selected and assigned into the separate group and combined group. Fifty-three patients in the separate group only received oral mitiginide, while other 53 patients in the combined group received oral mitiglinide and laster photocoagulation surgery. Before and after treatment, the FBG, 2hPBG, HbA1c, TC, TG, HDL-C, LDL-C, ET-1, VEGF, PEDF, ICAM-1, FMD of patients in the two groups were analyzed.Results: After treatment, the blood glucose and blood lipid indexes of patients in the two groups were improved significantly, and there was no statistical difference between the two groups. The ET-1, ICAM-1 and VEGF of patients in the two groups decreased, and the decrease of the combined group was more distinctly. The PEDF and FMD in the two groups all increased, and the combined group changed more obviously. The regression of the blood vessel and the recovery of visual acuity in the combined group were better than the separate group.Conclusions:Mitiglinide combined with laser photocoagulation can effectively improve the level of blood glucose and blood lipid, promote vascular endothelial function and inhibit the formation of retinal neovascularization so as to improve the visual acuity level.

  8. [Vascular endothelial Barrier Function].

    Science.gov (United States)

    Ivanov, A N; Puchinyan, D M; Norkin, I A

    2015-01-01

    Endothelium is an important regulator of selective permeability of the vascular wall for different molecules and cells. This review summarizes current data on endothelial barrier function. Endothelial glycocalyx structure, its function and role in the molecular transport and leukocytes migration across the endothelial barrier are discussed. The mechanisms of transcellular transport of macromolecules and cell migration through endothelial cells are reviewed. Special section of this article addresses the structure and function of tight and adherens endothelial junction, as well as their importance for the regulation of paracellular transport across the endothelial barrier. Particular attention is paid to the signaling mechanism of endothelial barrier function regulation and the factors that influence on the vascular permeability.

  9. Effects of Replenishing Qi, Promoting Blood Circulation and Resolving Phlegm on Vascular Endothelial Function and Blood Coagulation System in Senile Patients with Hyperlipemia

    Institute of Scientific and Technical Information of China (English)

    Yang Huimin; Han Libei; Sheng Tong; He Qiong; Liang Jinpu

    2006-01-01

    Objective: To observe the curative effect of the method of replenishing qi, promoting blood circulation and resolving phlegm on senile hyperlipemia and its effects on vascular endothelial function and blood coagulation system. Method: 96 patients with senile hyperlipemia were randomly divided into a treatment group and a of blood lipid, vascular endothelial function, blood coagulation system and safety. Results: After treatment,the treatment group was obviously superior to the control group (P<0.05) in reducing plasma total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as well as in the ratio of thromboxane B2 (TXB2) to 6-keto-prostaglandin F1α (6-keto-PGF1α), D-dimer (D-D) and fibrinogen (FIB). Conclusion: Danshen Jueming Granules have the effect of regulating metabolism of blood lipid, and improving vascular endothelial function and blood coagulation system in senile patients with hyperlipemia.

  10. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

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    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  11. Prostacyclin production by blood-contacting surfaces of endothelialized vascular prostheses.

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    Greisler, H P; Klosak, J J; McGurrin, J F; Endean, E D; Ellinger, J; Pozar, J D; Henderson, S C; Kim, D U

    1990-01-01

    This study examines prostacyclin production by blood-contacting surfaces within woven vascular prostheses of polydioxanone (PDS), polyglactin 910 (PG910), or Dacron interposed into rabbit infrarenal aortas. Grafts and normal aortic segments were explanted after 1, 3, and 6 months for pulsatile perfusion with Medium-199 for 60 minutes. Aliquots were removed serially for 6-keto-PGF1 alpha assay. After 30 minutes sodium arachidonate (10 micrograms/ml) was added. Specimens were studied by light microscopy, SEM and TEM. Patency in all three groups exceeded 90%. All three showed re-endothelialization at one month. Normal aorta produced low basal 6-keto-PGF1 alpha with a marked evanescent post arachidonate increase. Dacron did not differ from normal aorta. PG910 and PDS both produced significantly less 6-keto-PGF1 alpha post arachidonate at one month but both increased to normal by three months.

  12. Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia

    DEFF Research Database (Denmark)

    Håkansson, Gisela; Gesslein, Bodil; Gustafsson, Lotta

    2010-01-01

    Retinal ischemia arises from circulatory failure. As the retinal blood vessels are key organs in circulatory failure, our aim was to study the retinal vasculature separately from the neuroretina to elucidate the role of hypoxia-inducible factor (HIF) 1α and 1β and vascular endothelial growth factor...

  13. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

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    Shize Jiang

    Full Text Available The blood-brain barrier (BBB impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF on BBB permeability in Kunming (KM mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse, while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI. Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001. Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

  14. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets

    DEFF Research Database (Denmark)

    Werther, K; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2002-01-01

    . In corresponding blood samples, automated complete blood count was performed, and the number of each cell type was correlated to VEGF concentrations in plasma, serum and lysed whole blood. Finally, the impact of increasing clotting time on the release of VEGF to serum was analysed. RESULTS: Isolated neutrophils......AIM: The sources of increased vascular endothelial growth factor (VEGF) concentrations in peripheral blood from cancer patients are not known in detail. The aim of the present study was to evaluate correlations between the VEGF content in isolated leucocyte subpopulations and VEGF concentrations...... in plasma, serum and lysed whole blood. METHODS: In 51 colorectal cancer (CRC) patients, circulating T-lymphocytes, B-lymphocytes, monocytes, and granulocytes were isolated by means of immunomagnetic separation. Subsequently, the isolated cells were lysed and VEGF contents in the lysates were determined...

  15. Vascular Endothelial Growth Factor Increases during Blood-Brain Barrier-Enhanced Permeability Caused by Phoneutria nigriventer Spider Venom

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    Monique C. P. Mendonça

    2014-01-01

    Full Text Available Phoneutria nigriventer spider accidental envenomation provokes neurotoxic manifestations, which when critical, results in epileptic-like episodes. In rats, P. nigriventer venom (PNV causes blood-brain barrier breakdown (BBBb. The PNV-induced excitotoxicity results from disturbances on Na+, K+ and Ca2+ channels and glutamate handling. The vascular endothelial growth factor (VEGF, beyond its angiogenic effect, also, interferes on synaptic physiology by affecting the same ion channels and protects neurons from excitotoxicity. However, it is unknown whether VEGF expression is altered following PNV envenomation. We found that adult and neonates rats injected with PNV showed immediate neurotoxic manifestations which paralleled with endothelial occludin, β-catenin, and laminin downregulation indicative of BBBb. In neonate rats, VEGF, VEGF mRNA, and Flt-1 receptors, glutamate decarboxylase, and calbindin-D28k increased in Purkinje neurons, while, in adult rats, the BBBb paralleled with VEGF mRNA, Flk-1, and calbindin-D28k increases and Flt-1 decreases. Statistically, the variable age had a role in such differences, which might be due to age-related unequal maturation of blood-brain barrier (BBB and thus differential cross-signaling among components of the glial neurovascular unit. The concurrent increases in the VEGF/Flt-1/Flk-1 system in the cerebellar neuron cells and the BBBb following PNV exposure might imply a cytokine modulation of neuronal excitability consequent to homeostatic perturbations induced by ion channels-acting PNV neuropeptides. Whether such modulation represents neuroprotection needs further investigation.

  16. Association between glycemic control and morning blood surge with vascular endothelial dysfunction in type 2 diabetes mellitus patients

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    Rama Kumari Nuthalapati

    2016-01-01

    Full Text Available Objective: Morning blood pressure surge (MBPS is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and MBPS, and its effect on vascular injury in patients with type 2 diabetes mellitus (T2DM. The current study examined the association between glycemic control and MBPS and the involvement of MBPS in the development of vascular dysfunction in T2DM patients. Materials and Methods: One hundred and twenty-two consecutive T2DM outpatients from the Department of Cardiology and Endocrinology were enrolled in this study. We did MBPS in T2DM patients, 85 (male (69.7% patients and 37 (female patients (30.3%; mean age 60.1 ± 9.39; (n = 122 using 24 h ambulatory blood pressure monitoring and assessed vascular function by brachial artery flow-mediated dilation (FMD and nitroglycerin-mediated dilation (NMD. Results: The correlation between MBPS and various clinical variables were examined by single regression analysis in all subjects. MBPS showed significant and positive correlation with pulse rate (P = 0.01, fasting blood sugar (P = 0.002, and postprandial blood sugar (P = 0.05. To further confirm the association of insulin resistance (IR with MBPS in T2DM patients, we examined the correlation between homeostasis model assessment-IR (HOMA-IR, an established marker of IR and MBPS in diabetic (DM patients who were not taking insulin no significant association with MBPS in T2DM patients (P = 0.41, angiotensin-converting enzyme/angiotensin receptor blocker (P = 0.07. We examined the relationship between MBPS and vascular injury by measuring endothelium-dependent FMD and endothelium-independent NMD in T2DM patients. Among the various traditional risk factors for atherosclerosis such as DM duration (P = 0.04, platelet reactivity (P = 0.04 and morning surge (P = 0.002 emerged as significant factors. HOMA-IR was a negative correlation with FMD. Conclusions: The current study demonstrated that

  17. Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate (DOCA-salt hypertension

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    Haroldo A. Toque

    2013-07-01

    Full Text Available Enhanced arginase (ARG activity has been identified as a factor that reduces nitric oxide (NO production and impairs endothelial function in vascular pathologies. Using a gene deletion model, we investigated involvement of arginase isoforms (1 and 2 in hypertension and endothelial dysfunction in a mineralocorticoid-salt mouse model. Hypertension was induced in wild type (WT, partial ARG1+/- knockout (KO and complete ARG2-/- KO mice by uninephrectomy and DOCA-salt treatment for 6-weeks. (Control uninephrectomized mice drank tap water. After 2 wks of DOCA-salt treatment, systolic blood pressure (SBP was increased by ~15 mmHg in all mouse genotypes. SBP continued to rise in DOCA-salt WT and ARG2-/- mice to ~130 mmHg at 5-6 wks, whereas in ARG1+/- mice SBP waned toward control levels by 6 wks (109±4 vs 101±3 mmHg, respectively. DOCA-salt treatment in WT mice increased vascular ARG activity (aorta by 1.5-fold; mesenteric artery (MA by 2.6-fold and protein levels of ARG1 (aorta: 1.49-fold and MA: 1.73-fold versus WT Sham tissues. ARG2 protein increased in WT DOCA MA (by 2.15-fold but not in aorta compared to those of WT Sham tissues. Maximum endothelium-dependent vasorelaxation to acetylcholine was significantly reduced in DOCA-salt WT mice and largely or partially maintained in DOCA ARG1+/- and ARG2-/- mice vs their Sham controls. DOCA-salt augmented contractile responses to phenylephrine in aorta of all mouse genotypes. Additionally, treatment of aorta or MA from WT DOCA mice with arginase inhibitor ABH (100 µM improved endothelium-mediated vasorelaxation. DOCA-salt induced coronary perivascular fibrosis (increased by 2.1-fold in WT was prevented in ARG1+/- and reduced in ARG2-/- mice. In summary, arginase is involved in murine DOCA-salt induced impairment of vascular function and hypertension and may represent a novel target for antihypertensive therapy.

  18. Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression

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    Takahashi, Tetsuya; Fujimura, Masatake; Koyama, Misaki; Kanazawa, Masato; Usuki, Fusako; Nishizawa, Masatoyo; Shimohata, Takayoshi

    2017-01-01

    Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity. PMID:28118383

  19. Constructing a blood vessel on the porous scaffold modified with vascular endothelial growth factor and basic fibroblast growth factor

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    Sevostyanova, V. V.; Matveeva, V. G.; Antonova, L. V.; Velikanova, E. A.; Shabaev, A. R.; Senokosova, E. A.; Krivkina, E. O.; Vasyukov, G. Yu.; Glushkova, T. V.; Kudryavtseva, Yu. A.; Barbarash, O. L.; Barbarash, L. S.

    2016-11-01

    Incorporation of the growth factors into biodegradable polymers is a promising approach for the fabrication of tissue-engineered vascular grafts. Here we blended poly(ɛ-caprolactone) (PCL) with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) following incorporation of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) and then fabricated electrospun 2 mm diameter vascular grafts. Grafts without the growth factors were used as a control group. Structure of the grafts was assessed utilizing scanning electron microscopy. We further implanted our grafts into rat abdominal aorta for 1 and 3 months with the aim to test endothelialization, cell infiltration, and patency in vivo. Histological and immunofluorescence examination demonstrated enhanced endothelialization and cell infiltration of the grafts with either VEGF or bFGF compared to those without the growth factors. Grafts with VEGF showed higher patency compared to those with bFGF; however, bFGF promoted migration of smooth muscle cells and fibroblasts into the graft. Therefore, we conclude that incorporation of VEGF and bFGF into the inner and medial/outer layer, respectively, can be a promising option for the fabrication of tissue-engineered vascular grafts.

  20. Lymphatic vessels growing apart from blood vessels in transplanted corneas after the blockade of vascular endothelial growth factor C

    Institute of Scientific and Technical Information of China (English)

    Ye Hui; Yan Hao; Zhong Lei; Wang Tao; Deng Juan; Ling Shi-qi

    2016-01-01

    BACKGROUND:Corneal lymphangiogenesis is beneficial to the transport of corneal antigenic materials, and accelerates the process of antigen presentation, thereby playing an important role in corneal immunity. However, due to the paral el outgrowth of corneal blood and lymphatic vessels in transplanted corneas, it is often difficult to accurately evaluate the role of corneal lymphatic vessels in allograft rejection. OBJECTIVE:To explore the development of corneal lymphangiogenesis and angiogenesis in transplanted rat corneas after the blockade of vascular endothelial growth factor C (VEGF-C). METHODS:130 rats used to establish corneal al ogenic transplantation models were equally randomized into two groups:the anti-VEGF-C group and the control group. VEGF-C was blocked in the anti-VEGF-C group by intraperitoneal injection of neutralizing monoclonal anti-VEGF-C antibody every other day for 2 consecutive weeks. Meanwhile, rats in control groups received intraperitoneal injections of saline. Corneal angiogenesis and lymphangiogenesis were characterized using whole mount immunofluorescence, and the immune rejection of the grafts was evaluated by scoring the rejection index (RI). In addition, the expression of VEGF-C was examined by real-time PCR. The relationship of corneal lymphangiogenesis and angiogenesis to RI in transplanted corneas was also characterized. RESULTS AND CONCLUSION:VEGF-C expression was markedly downregulated after VEGF-C blockade. Corneal lymphangiogenesis developed in parallel with corneal angiogenesis in the control group. While there was a mild reduction in blood vessel area (BVA) and a significant decrease in lymphatic vessel area (LVA) in the anti-VEGF-C group (P0.05). the graft survival time in the anti-VEGF-C group was significantly increased compared with that in the control group (P<0.05). Our results show that the outgrowth of lymphatic vessels is separated from that of blood vessels in transplanted corneas by blocking VEGF-C. The blockade

  1. Regulatory effect of vascular endothelial growth factor on blood spinal cord barrier in presyrinx state of experimental syringomyelia

    Institute of Scientific and Technical Information of China (English)

    Jianfeng Li; Changrong Zhou; Haiying Liu; Penghui Xing

    2008-01-01

    BACKGROUND: Vascular endothelial growth factor (VEGF) is able to regulate blood spinal cord barrier function as well as influence neovascularization and cause edema. OBJECTIVE: Through establishment of a rabbit model of syringomyelia, to explore the correlation between VEGF protein and mRNA expressions and function of blood spinal cord barrier and edema degree of spinal cord in presyrinx state. DESIGN, TIME AND SETTING: Randomized controlled animal study was performed in the Tumor Institute of the Fourth Hospital, Hebei Medical University from January to June 2007. MATERIALS: A total of 0.6 mL Kaolin solution (250 g/L, 37 ℃) was injected into the cisterna magna of 40 rabbits in the kaolin group to establish syringomyelia models. Goat anti-rabbit VEGF monoclonal antibody was provided by DIACLONE Company, USA; RT-PCR related reagents were provided by Huamei Bioengineering Co., Ltd., Beijing.METHODS: Sixty Chinese white rabbits were divided randomly into two groups: Kaolin group (n = 40) and control group (n = 20). Physiological saline (0.6 mL at 37 ℃) was injected in rabbits of control group. On days 1, 3, 7, 14 and 21 after kaolin injection, cervical cords samples were harvested after sacrifice of animal. MAIN OUTCOME MEASURES: VEGF protein and mRNA expressions were detected by immunohistochemistry and RT-PCR on days 1, 3, 7, 14, and 21 after kaolin injection. A quantitative analysis of blood spinal cord barrier function was performed by Evans blue technique. Water content of the spinal cord was measured by dry-wet weight technique. The correlation between the expression of VEGF protein and mRNA and the function of blood spinal cord barrier in the upper cervical cord of the presyrinx state was analyzed by linear correlation analysis. RESULTS: The water content and Evans blue content increased in the kaolin group on days 1 and 3 postoperatively compared with the control group (F= 7.387, 61.35, P< 0.05, 0.01), and reached a peak on day 7 (F= 135.94, 528.35, P< 0

  2. The association between preoperative concentration of soluble vascular endothelial growth factor, perioperative blood transfusion, and survival in patients with primary colorectal cancer

    DEFF Research Database (Denmark)

    Werther, K; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2001-01-01

    OBJECTIVE: To investigate a possible association between the preoperative concentration of soluble vascular endothelial growth factor (sVEGF), perioperative blood transfusion, and survival in patients operated on for colorectal cancer. DESIGN: Retrospective study. SETTING: University hospital......, Denmark. SUBJECTS: 614 patients operated on for primary colorectal cancer. MAIN OUTCOME MEASURES: Association between preoperative blood transfusion and preoperative concentration of sVEGF. Association between perioperative blood transfusion and survival. RESULTS: Blood transfused up to one month before...... preoperative serum samples were obtained was significantly (p = 0.02) associated with high preoperative concentrations of sVEGF. The frequency of perioperative blood transfusion was significantly (p = 0.0007) higher in patients with rectal cancer than in patients with colon cancer. A multivariate analysis...

  3. Specific Accumulation of Tumor-Derived Adhesion Factor in Tumor Blood Vessels and in Capillary Tube-Like Structures of Cultured Vascular Endothelial Cells

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    Akaogi, Kotaro; Okabe, Yukie; Sato, Junji; Nagashima, Yoji; Yasumitsu, Hidetaro; Sugahara, Kazuyuki; Miyazaki, Kaoru

    1996-08-01

    Tumor-derived adhesion factor (TAF) was previously identified as a cell adhesion molecule secreted by human bladder carcinoma cell line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in human normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF was specifically accumulated in small blood vessels and capillaries within and adjacent to tumor nests, but not in those in normal tissues. Tumor blood vessel-specific staining of TAF was observed in various human cancers, such as esophagus, brain, lung, and stomach cancers. Double immunofluorescent staining showed apparent colocalization of TAF and type IV collagen in the vascular basement membrane. In vitro experiments demonstrated that TAF preferentially bound to type IV collagen among various extracellular matrix components tested. In cell culture experiments, TAF promoted adhesion of human umbilical vein endothelial cells to type IV collagen substrate and induced their morphological change. Furthermore, when the endothelial cells were induced to form capillary tube-like structures by type I collagen, TAF and type IV collagen were exclusively detected on the tubular structures. The capillary tube formation in vitro was prevented by heparin, which inhibited the binding of TAF to the endothelial cells. These results strongly suggest that TAF contributes to the organization of new capillary vessels in tumor tissues by modulating the interaction of endothelial cells with type IV collagen.

  4. Opiates Upregulate Adhesion Molecule Expression in Brain MicroVascular Endothelial Cells (BMVEC: Implications for Altered Blood Brain Barrier (BBB Permeability

    Directory of Open Access Journals (Sweden)

    Madhavan P.N. Nair

    2006-01-01

    Full Text Available The blood-brain barrier (BBB is an intricate cellular system composed of vascular endothelial cells and perivascular astrocytes that restrict the passage of immunocompetent cells into the central nervous system (CNS. Expression of the adhesion molecules, intercellular adhesion molecule 1 (ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1 on brain microvascular endothelial cells (BMVEC and their interaction with human immunodeficiency virus (HIV-1 viral proteins may help enhance viral adhesion and virus-cell fusion resulting in increased infectivity. Additionally, transmigration through the BBB is facilitated by both endothelial and monocyte/macrophage-derived nitric oxide (NO. Dysregulated production of NO by BMVEC due to opiates and HIV-1 viral protein interactions play a pivotal role in brain endothelial injury, resulting in the irreversible loss of BBB integrity, which may lead to enhanced infiltration of virus-carrying cells across the BBB. Opioids act as co-factors in the neuropathogenesis of HIV-1 by facilitating BBB dysfunction however, no studies have been done to investigate the role of opiates alone or in combination with HIV-1 viral proteins on adhesion molecule expression in BMVEC. We hypothesize that opiates such as heroin and morphine in conjunction with the HIV-1 viral protein gp120 increase the expression of adhesion molecules ICAM-1 and VCAM-1 and these effects are mediated via the modulation of NO. Results show that opiates alone and in synergy with gp120 increase both the genotypic and phenotypic expression of ICAM-1 and VCAM-1 by BMVEC, additionally, these opiate induced effects may be the result of increased NO production. These studies will provide a better understanding of how opiate abuse in conjunction with HIV-1 infection facilitates the breakdown of the BBB and exacerbates the neuropathogenesis of HIV-1. Elucidation of the mechanisms of BBB modulation will provide new therapeutic approaches to maintain BBB integrity

  5. VASCULAR ENDOTHELIAL INJURIES AND CHANGES OF BLOOD COAGULATION AND FIBRINOLYSIS INDEXES IN PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME

    Institute of Scientific and Technical Information of China (English)

    Xiao-lin He; Zhi Liu; Shu-yue Xia

    2004-01-01

    Objective To study endothelial damage by observing changes of circulating endothelial cells (CECs) in blood, coagulation and fibrinolysis index in patients with acute respiratory distress syndrome.Methods CECs were separated by isopycnic centrifugation method in 14 patients with acute lung injury (ALI), 7patients with acute respiratory distress syndrome (ARDS), 10 intensive care unit (ICU) controls, and 15 healthy controls.Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FG), fibrin degradation products (FDP), and D-dimer were examined simultaneously. Acute physiology and chronic health evaluation (APACHE) Ⅱ and lung injury score (LIS) were recorded to evaluate severity of illness and lung injury.Results (1) The number of CECs in ALI (10.4 ± 2.3 ) and ARDS groups ( 16.1 ± 2.7) was higher than that in the healthy (1.9 ± 0.5) (P < 0.01). In both ALI and ARDS, the number of CECs correlated with APACHE Ⅱ (r = 0.55, P < 0.05 and r =0.62, P < 0.05, respectively) and LIS (r = 0.60, P < 0.05 and r = 0.53, P < 0.05, respectively). CEC number was negatively correlated with PaO2 in ALI and ARDS (r=-0.49, P< 0.05 and r=-0.64, P< 0.05, respectively). (2) The level of FDP and D-dirmer were higher in ALI and ARDS patients than that in ICU and healthy control groups (P<0.05). The level of FG in ARDS group was significantly higher than in the ICU and healthy control groups (P < 0.05). But in ALI group, the level of FG was significantly higher than only healthy control group (P < 0.05).Conclusions Endothelial cell damage occurs in ARDS patients, which may play a major role in the pathophysiology of ARDS. Changes of endothelial cell activation and damage markers, such as CECs, plasma coagulation and fibrinolysis index,to some extent reflect severity of illness and lung injury in ARDS.

  6. The influence of genotype on vascular endothelial growth factor and regulation of myocardial collateral blood flow in patients with acute and chronic coronary heart disease

    DEFF Research Database (Denmark)

    Ripa, R.S.; Jorgensen, E.; Baldazzi, F.;

    2009-01-01

    OBJECTIVE: To test the hypothesis that mutations in the vascular endothelial growth factor (VEGF) gene are associated with plasma concentration of VEGF and subsequently the ability to influence coronary collateral arteries in patients with coronary heart disease (CHD). METHODS: Blood samples from...... patients with chronic ischemic heart disease (n=53) and acute coronary syndrome (n=61) were analysed. Coronary collaterals were scored from diagnostic biplane coronary angiograms. RESULTS: The plasma concentration of VEGF was increased in patients with acute compared to chronic CHD (p=0.01). The genotype......-1154 and coronary collateral size (p=0.03) and a significant association between the VEGF plasma concentration and the collateral size (p=0.03). CONCLUSION: VEGF plasma concentration seems related to coronary collateral function in patients with CHD. The results did not support the hypothesis...

  7. Circulating vascular endothelial growth factor during the normal menstrual cycle

    NARCIS (Netherlands)

    Kusumanto, YH; Hospers, GAP; Sluiter, WJ; Dam, WA; Meijer, C; Mulder, NH

    2004-01-01

    Background: The purpose of the study was to investigate whether cycle-related variations in circulating Vascular Endothelial Growth Factor (VEGF) levels would increase the metastatic potential at specific times during the menstrual cycle. Materials and Methods: VEGF levels in serum and whole blood w

  8. Vascular endothelial dysfunction and pharmacological treatment

    Institute of Scientific and Technical Information of China (English)

    Jin; Bo; Su

    2015-01-01

    The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smo-king, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide(NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.

  9. Down-regulation of pigment epithelium-derived factor in uveitic lesion associates with focal vascular endothelial growth factor expression and breakdown of the blood-retinal barrier.

    Science.gov (United States)

    Deeg, Cornelia A; Altmann, Frank; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius

    2007-05-01

    Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Identifying biological markers or pathways associated with this disease may allow the understanding of its pathogenesis at a molecular level. The vitreous is the body fluid closest to the disease-affected tissue and possibly also an effector of pathological processes relevant for ERU. Surgical removal of vitreous leads to cessation of relapses in spontaneous uveitis of both man and horse, therefore vitreous composites are likely to contribute to disease progression. Uveitic vitreous is likely to contain potential biomarkers in relatively undiluted quantities. With the goal to identify these markers, we systematically compared vitreous from healthy and disease-affected eyes by proteomic profiling. Nine differentially expressed proteins were identified, that are functionally related to immune response, inflammation, and maintenance of the blood-retinal barrier. One of these, pigment epithelium-derived factor, a protein involved in maintaining a proper blood-retina barrier as well as protecting from neoangiogenesis was additionally found to be down-regulated within uveitic retinal lesions whereas, conversely, vascular endothelial growth factor was found to be up-regulated at these sites. Together, these changes point to as of yet undiscovered biological pathways involved in the pathogenesis of this autoimmune disease.

  10. Anti-human Vascular Endothelial Growth Factor (VEGF) Antibody Selection for Immunohistochemical Staining of Proliferating Blood Vessels

    NARCIS (Netherlands)

    C.M. van der Loos; L.B. Meijer-Jorna; M.E.C. Broekmans; H.P.H.M. Ploegmakers; P. Teeling; O.J. de Boer; A.C. van der Wal

    2010-01-01

    Nine commercially available VEGF antibodies are investigated for their ability to immunostain vascular malformations (VM) with or without immature capillary proliferation. First, all antibodies were optimized for their performance in immunohistochemistry with placenta and colon adenocarcinoma as pos

  11. Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placentalischemia-induced hypertension.

    Science.gov (United States)

    Gilbert, Jeffrey S; Verzwyvelt, Joseph; Colson, Drew; Arany, Marietta; Karumanchi, S Ananth; Granger, Joey P

    2010-02-01

    Antagonism of vascular endothelial growth factor (VEGF) signaling by soluble fms-like tyrosine kinase 1 occurs during preeclampsia and is proposed to play an important role in the pathogenesis of preeclampsia. We reported recently that hypertension associated with chronic reductions in uteroplacental perfusion pressure (RUPP) is associated with increased soluble fms-like tyrosine kinase 1 and decreased free VEGF. Whether restoration of circulating VEGF can restore renal function and chronically decrease arterial pressure associated with placental ischemia remains unknown. We hypothesized that chronic infusion of VEGF(121) would attenuate hypertension, increase glomerular filtration rate, and reverse the endothelial dysfunction associated with chronic RUPP. VEGF(121) (at either 90 or 180 microg/kg per day) was administered for 5 days via osmotic minipump placed IP. Mean arterial pressure, renal function, and tissues were obtained on day 19 of pregnancy from RUPP+VEGF, RUPP, and normal pregnant dams. Mean arterial pressure was increased in the RUPP (131+/-3 mm Hg) compared with the normal pregnant (102+/-1 mm Hg) rats, and infusion of VEGF(121) resolved the hypertension (105+/-5 mm Hg). Glomerular filtration rate was decreased in the RUPP dams (1.5+/-0.3 mL/min) and restored to normal pregnant levels (3.1+/-0.5 mL/min) by VEGF(121) treatment (3.1+/-0.4 mL/min). Effective renal plasma flow, decreased by RUPP, was also increased by VEGF(121) infusion. Relaxation to acetylcholine was enhanced by the VEGF treatment (Phigh blood pressure associated with placental ischemia. The present results suggest that VEGF(121) may be a candidate molecule for management of preeclampsia and its related complications.

  12. KLF2 and KLF4 control endothelial identity and vascular integrity

    Science.gov (United States)

    Sangwung, Panjamaporn; Zhou, Guangjin; Nayak, Lalitha; Chan, E. Ricky; Kang, Dong-Won; Zhang, Rongli; Lu, Yuan; Sugi, Keiki; Fujioka, Hisashi; Shi, Hong; Lapping, Stephanie D.; Ghosh, Chandra C.; Higgins, Sarah J.; Parikh, Samir M.; Jain, Mukesh K.

    2017-01-01

    Maintenance of vascular integrity in the adult animal is needed for survival, and it is critically dependent on the endothelial lining, which controls barrier function, blood fluidity, and flow dynamics. However, nodal regulators that coordinate endothelial identity and function in the adult animal remain poorly characterized. Here, we show that endothelial KLF2 and KLF4 control a large segment of the endothelial transcriptome, thereby affecting virtually all key endothelial functions. Inducible endothelial-specific deletion of Klf2 and/or Klf4 reveals that a single allele of either gene is sufficient for survival, but absence of both (EC-DKO) results in acute death from myocardial infarction, heart failure, and stroke. EC-DKO animals exhibit profound compromise in vascular integrity and profound dysregulation of the coagulation system. Collectively, these studies establish an absolute requirement for KLF2/4 for maintenance of endothelial and vascular integrity in the adult animal. PMID:28239661

  13. Vascular endothelial cells and dysfunctions: role of melatonin.

    Science.gov (United States)

    Rodella, Luigi Fabrizio; Favero, Gaia; Foglio, Eleonora; Rossini, Claudia; Castrezzati, Stefania; Lonati, Claudio; Rezzani, Rita

    2013-01-01

    Several pathological conditions, including hypertension, atherosclerosis, diabetes, ischemia/reperfusion injury and nicotine-induced vasculopathy, are associated with vascular endothelial dysfunction characterized by altered secretory output of endothelial cells. Therefore there is a search for molecules and interventions that could restore endothelial function, in particular augmenting NO production, reducing the generation of free radicals and vasoconstrictors and preventing undesired inflammation. The pineal hormone melatonin exhibits several endothelium protective properties: it scavenges free radicals, activates antioxidant defence enzymes, normalizes lipid and blood pressure profile and increases NO bioavailability. Melatonin improved vascular function in experimental hypertension, reducing intimal infiltration and restoring NO production. Melatonin improved the NO pathway also in animal models for the study of diabetes and prevented NO down-regulation and adhesive molecules up-regulation in nicotine-induced vasculopathy. The protection against endothelial damage, vasoconstriction, platelet aggregation and leukocyte infiltration might contribute to the beneficial effects against ischemia-reperfusion injury by melatonin. Therefore, melatonin administration has endothelium-protective potential in several pathological conditions. Nevertheless, it still needs to be established, whether melatonin is able to revert already established endothelial dysfunction in these conditions.

  14. Cytoskeleton, cytoskeletal interactions, and vascular endothelial function

    Directory of Open Access Journals (Sweden)

    Wang J

    2012-12-01

    Full Text Available Jingli Wang,1 Michael E Widlansky1,21Department of Medicine, Cardiovascular Medicine Division, 2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, USAAbstract: Far from being inert, the vascular endothelium is a critical regulator of vascular function. While the endothelium participates in autocrine, paracrine, and endocrine signaling, it also transduces mechanical signals from the cell surface involving key cell structural elements. In this review, we discuss the structure of the vascular endothelium and its relationship to traditional cardiovascular risk factors and clinical cardiovascular events. Further, we review the emerging evidence that cell structural elements, including the glycocalyx, intercellular junctions, and cytoskeleton elements, help the endothelium to communicate with its environment to regulate vascular function, including vessel permeability and signal transduction via nitric oxide bioavailability. Further work is necessary to better delineate the regulatory relationships between known key regulators of vascular function and endothelial cell structural elements.Keywords: endothelium, shear stress, eNOS, cardiovascular risk factors, glycocalyx

  15. Genistein Attenuates Vascular Endothelial Impairment in Ovariectomized Hyperhomocysteinemic Rats

    Directory of Open Access Journals (Sweden)

    Panpan Zhen

    2012-01-01

    Full Text Available Hyperhomocysteinemia (HHcy is a well-known independent risk factor for vascular diseases in the general population. This study was to explore the effect of genistein (GST, a natural bioactive compound derived from legumes, on HHcy-induced vascular endothelial impairment in ovariectomized rats in vivo. Thirty-two adult female Wistar rats were assigned randomly into four groups (n=8: (a Con: control; (b Met: 2.5% methionine diet; (c OVX + Met: ovariectomy + 2.5% methionine diet; (d OVX + Met + GST: ovariectomy + 2.5% methionine diet + supplementation with genistein. After 12 wk of different treatment, the rats' blood, toracic aortas and liver samples were collected for analysis. Results showed that high-methionine diet induced both elevation of plasma Hcy and endothelial dysfunction, and ovariectomy deteriorated these injuries. Significant improvement of both functional and morphological changes of vascular endothelium was observed in OVX + Met + GST group; meanwhile the plasma Hcy levels decreased remarkably. There were significant elevations of plasma ET-1 and liver MDA levels in ovariectomized HHcy rats, and supplementation with genistein could attenuate these changes. These results implied that genistein could lower the elevated Hcy levels, and prevent the development of endothelial impairment in ovariectomized HHcy rats. This finding may shed a novel light on the anti-atherogenic activities of genistein in HHcy patients.

  16. Vascular endothelial dysfunction: a tug of war in diabetic nephropathy?

    Science.gov (United States)

    Balakumar, Pitchai; Chakkarwar, Vishal Arvind; Krishan, Pawan; Singh, Manjeet

    2009-03-01

    Vascular endothelium regulates vascular tone and maintains free flow of blood in vessels. Vascular endothelial dysfunction (VED) results in reduced activation of endothelial nitric oxide synthase (eNOS), reduced generation and bioavailability of nitric oxide (NO) and increased production of reactive oxygen species (ROS). The eNOS uncoupling in VED leads to eNOS mediated production of ROS that further damage the endothelial cells by upregulating the proinflammatory mediators and adhesion molecules. VED has been associated in the pathogenesis of hypertension, atherosclerosis, coronary artery diseases, diabetes mellitus and nephropathy. Diabetes is a chronic metabolic disorder characterized by hyperglycemia followed by micro and macrovascular complications. A correlation between diabetes and VED has been demonstrated in various studies. The downregulation of eNOS in diabetes has been noted to accelerate diabetic nephropathy. Moreover, various endogenous vasoconstrictors are also upregulated in diabetic nephropathy. VED has been shown to be involved in diabetic nephropathy by inducing nodular glomerulosclerosis followed by glomerular basement membrane thickness and mesangial expansion, which ultimately decline glomerular filtration rate (GFR). Thus it is suggested that diabetes-induced VED could be one of the culprits involved in the pathogenesis of diabetic nephropathy.

  17. Correlation of vascular endothelial growth factor to permeability of blood-brain barrier and brain edema during high-altitude exposure

    Institute of Scientific and Technical Information of China (English)

    Qiquan Zhou; Chang'e Liu; Jing Wang; Yunli Wang; Bo Zhou

    2009-01-01

    BACKGROUND:Many studies have evaluated the role of vascular endothelial growth factor (VEGF) in traumatic brain edema and hemorrhagic brain edema.OBJECTIVE:To observe the effects of VEGF expression on permeability of the blood-brain barrier (BBB) during high-altitude and hypoxia exposure,and to investigate the correlation between VEGF expression and BBB permeability with regard to Evans blue staining and brain edema during high-altitude exposure.DESIGN,TIME AND SETTING:The randomized,controlled,animal study was performed at the Tanggula Etape,Central Laboratory of Chengdu Medical College,and Central Laboratory of General Hospital of Chengdu Military Area Command of Chinese PLA,China,from July 2003 to November 2004.MATERIALS:Quantitative RT-PCR kit (Sigma,USA),VEGF ELISA kit (Biosource,USA),and Evans blue (Jingchun,China) were acquired for this study.METHODS:A total of 180 Wistar rats were equally and randomly assigned to 15 groups:low-altitude (500 m),middle-altitude (2 880 m),high-altitude (4 200 m),super-high-altitude (5 000 m),1,3,5,7,9,11,13,15,17,19,and 21 days of super high-altitude exposure.Wistar rats were exposed to various altitude gradients to establish a hypoxia model.MAIN OUTCOME MEASURES:Brain water content was calculated according to the wet-to-dry weight ratio.BBB permeability to Evans blue was determined by colorimetric method.VEGF mRNA and protein levels in brain tissues were detected using RT-PCR and double-antibody sandwich ELISA.RESULTS:Brain water content,BBB permeability to Evans blue,and VEGF mRNA and protein levels in brain tissues increased with increasing altitude and prolonged exposure to altitude.The greatest increase was determined on day 9 upon ascending 5 000 m.Simultaneously,VEGF expression positively correlated to BBB permeability of Evans blue and brain water content (r=0.975,0.917,P<0.01).CONCLUSION:Increased VEGF protein and mRNA expression was responsible for increased BBB permeability,which may be an important mechanism

  18. Blood Flow Restricted Exercise and Vascular Function

    Directory of Open Access Journals (Sweden)

    Masahiro Horiuchi

    2012-01-01

    Full Text Available It is established that regular aerobic training improves vascular function, for example, endothelium-dependent vasodilatation and arterial stiffness or compliance and thereby constitutes a preventative measure against cardiovascular disease. In contrast, high-intensity resistance training impairs vascular function, while the influence of moderate-intensity resistance training on vascular function is still controversial. However, aerobic training is insufficient to inhibit loss in muscular strength with advancing age; thus, resistance training is recommended to prevent sarcopenia. Recently, several lines of study have provided compelling data showing that exercise and training with blood flow restriction (BFR leads to muscle hypertrophy and strength increase. As such, BFR training might be a novel means of overcoming the contradiction between aerobic and high-intensity resistance training. Although it is not enough evidence to obtain consensus about impact of BFR training on vascular function, available evidences suggested that BFR training did not change coagulation factors and arterial compliance though with inconsistence results in endothelial function. This paper is a review of the literature on the impact of BFR exercise and training on vascular function, such as endothelial function, arterial compliance, or other potential factors in comparison with those of aerobic and resistance training.

  19. Glycoconjugates and Related Molecules in Human Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Norihiko Sasaki

    2013-01-01

    Full Text Available Vascular endothelial cells (ECs form the inner lining of blood vessels. They are critically involved in many physiological functions, including control of vasomotor tone, blood cell trafficking, hemostatic balance, permeability, proliferation, survival, and immunity. It is considered that impairment of EC functions leads to the development of vascular diseases. The carbohydrate antigens carried by glycoconjugates (e.g., glycoproteins, glycosphingolipids, and proteoglycans mainly present on the cell surface serve not only as marker molecules but also as functional molecules. Recent studies have revealed that the carbohydrate composition of the EC surface is critical for these cells to perform their physiological functions. In this paper, we consider the expression and functional roles of endogenous glycoconjugates and related molecules (galectins and glycan-degrading enzymes in human ECs.

  20. Biophysical Cueing and Vascular Endothelial Cell Behavior

    Directory of Open Access Journals (Sweden)

    Joshua A. Wood

    2010-03-01

    Full Text Available Human vascular endothelial cells (VEC line the vessels of the body and are critical for the maintenance of vessel integrity and trafficking of biochemical cues. They are fundamental structural elements and are central to the signaling environment. Alterations in the normal functioning of the VEC population are associated with a number of vascular disorders among which are some of the leading causes of death in both the United States and abroad. VECs attach to their underlying stromal elements through a specialization of the extracellular matrix, the basement membrane. The basement membrane provides signaling cues to the VEC through its chemical constituents, by serving as a reservoir for cytoactive factors and through its intrinsic biophysical properties. This specialized matrix is composed of a topographically rich 3D felt-like network of fibers and pores on the nano (1–100 nm and submicron (100–1,000 nm size scale. The basement membrane provides biophysical cues to the overlying VECs through its intrinsic topography as well as through its local compliance (relative stiffness. These biophysical cues modulate VEC adhesion, migration, proliferation, differentiation, and the cytoskeletal signaling network of the individual cells. This review focuses on the impact of biophysical cues on VEC behaviors and demonstrates the need for their consideration in future vascular studies and the design of improved prosthetics.

  1. Research of the correlation between estrogen and blood stasis from the vascular endothelial function%从血管内皮功能探讨雌激素与血瘀关联性的研究

    Institute of Scientific and Technical Information of China (English)

    甘卫冬; 眭承志

    2014-01-01

    Blood stasis is closely related to osteoporosis.The modern material and basic research of the pathological changes of blood stasis syndrome is a hot topic today.Studies have shown that the formation of blood stasis is closely related to the vascular endothelial-associated factors.Estrogen can affect the pathological changes of blood stasis syndrome by promoting the expression of vasodilation activity factors such as NO and PGI2, and inhibiting the expression of vascular contraction factors such as ET, Ang II, and TXA2.Estrogen may affected the occurrence of osteoporosis by improving blood stasis.%血瘀与骨质疏松关系密切。血瘀证病理变化的现代物质基础研究是当今研究的一个热点。研究表明血管内皮相关因子与血瘀的形成关系密切,雌激素通过促进NO、PGI2等血管舒张活性因子的表达,抑制ET、Ang Ⅱ、TXA2等血管收缩因子表达而对血瘀证病理变化有一定影响。雌激素可能通过改善血瘀而影响骨质疏松的发生。

  2. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells.

    Science.gov (United States)

    Nojiri, Takashi; Hosoda, Hiroshi; Tokudome, Takeshi; Miura, Koichi; Ishikane, Shin; Otani, Kentaro; Kishimoto, Ichiro; Shintani, Yasushi; Inoue, Masayoshi; Kimura, Toru; Sawabata, Noriyoshi; Minami, Masato; Nakagiri, Tomoyuki; Funaki, Soichiro; Takeuchi, Yukiyasu; Maeda, Hajime; Kidoya, Hiroyasu; Kiyonari, Hiroshi; Shioi, Go; Arai, Yuji; Hasegawa, Takeshi; Takakura, Nobuyuki; Hori, Megumi; Ohno, Yuko; Miyazato, Mikiya; Mochizuki, Naoki; Okumura, Meinoshin; Kangawa, Kenji

    2015-03-31

    Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.

  3. Blood flow controls bone vascular function and osteogenesis

    Science.gov (United States)

    Ramasamy, Saravana K.; Kusumbe, Anjali P.; Schiller, Maria; Zeuschner, Dagmar; Bixel, M. Gabriele; Milia, Carlo; Gamrekelashvili, Jaba; Limbourg, Anne; Medvinsky, Alexander; Santoro, Massimo M.; Limbourg, Florian P.; Adams, Ralf H.

    2016-01-01

    While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system. PMID:27922003

  4. Damage of vascular endothelial barrier induced by explosive blast and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Wang; Jing Chen

    2016-01-01

    In recent years,injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities.Tear.bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage.Vascular endothelial barrier is the main defense of tissues and organs' integrity.This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier,blood-air barrier,and intestinal vascular barrier impairments.In addition,the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damage resulting from explosive blast.

  5. Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain.

    Science.gov (United States)

    Morita, Shoko; Furube, Eriko; Mannari, Tetsuya; Okuda, Hiroaki; Tatsumi, Kouko; Wanaka, Akio; Miyata, Seiji

    2015-03-01

    The sensory circumventricular organs (CVOs), which comprise the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO) and the area postrema (AP), lack a typical blood-brain barrier (BBB) and monitor directly blood-derived information to regulate body fluid homeostasis, inflammation, feeding and vomiting. Until now, almost nothing has been documented about vascular features of the sensory CVOs except fenestration of vascular endothelial cells. We therefore examine whether continuous angiogenesis occurs in the sensory CVOs of adult mouse. The angiogenesis-inducing factor vascular endothelial growth factor-A (VEGF-A) and the VEGF-A-regulating transcription factor hypoxia-inducible factor-1α were highly expressed in neurons of the OVLT and SFO and in both neurons and astrocytes of the AP. Expression of the pericyte-regulating factor platelet-derived growth factor B was high in astrocytes of the sensory CVOs. Immunohistochemistry of bromodeoxyuridine and Ki-67, a nuclear protein that is associated with cellular proliferation, revealed active proliferation of endothelial cells. Moreover, immunohistochemistry of caspase-3 and the basement membrane marker laminin showed the presence of apoptosis and sprouting of endothelial cells, respectively. Treatment with the VEGF receptor-associated tyrosine kinase inhibitor AZD2171 significantly reduced proliferation and filopodia sprouting of endothelial cells, as well as the area and diameter of microvessels. The mitotic inhibitor cytosine-b-D-arabinofuranoside reduced proliferation of endothelial cells and the vascular permeability of blood-derived low-molecular-weight molecules without changing vascular area and microvessel diameter. Thus, our data indicate that continuous angiogenesis is dependent on VEGF signaling and responsible for the dynamic plasticity of vascular structure and permeability.

  6. Effect of Chinese Drugs for Promoting Blood Circulation and Eliminating Blood Stasis on Vascular Endothelial Growth Factor Expression in Rabbits with Glucocorticoid-induced Ischemic Necrosis of Femoral Head

    Institute of Scientific and Technical Information of China (English)

    QI Zhen-xi; CHEN Lei

    2009-01-01

    Objective:To probe into the mechanism of Chinese drugs for promoting blood circulation and eliminating blood stasis in the prevention and treatment of glueocorticoid-induced ischemic necrosis of femoral head.Methods: Thirty New Zealand adult white rabbits were randomly divided into a normal control group (n=5)and a model group (n=25). Hydroxyprednisone acetate was intramuscularly administered to the rabbits in the model group in a dosage of 7.5 mg/kg, twice per week for 6 weeks, to induce ischemic necrosis of femoral head and normal saline of the equal volume was intramuscularly administered to the rabbits in the normal control group, twice per week for 6 weeks. Then, the 5 rabbits from the normal control group and 5 rabbits selected randomly from the model group were sacrificed and the changes in histopathology and the expression of Vascular Endothelial Growth Factor (VEGF) were observed. The other 20 rabbits in the model group were randomly divided into the treatment group 1 and the treatment group 2, and the control group 1 and the control group 2, 5 rabbits in every group. Taohong Siwu Tang (桃红四物汤 Decoction of Four Drugs with Addition of Peach Kernel and Safflower) was orally administered to the rabbits in the treatment group 1 and the treatment group 2 in a dosage of 7 ml/kg, once daily and normal saline of the equal volume was orally administered to the rabbits in the control groupl and the control group, 2 once daily. After 10 weeks the rabbits in the treatment group 1 and the control group 1 were sacrificed and after 13 weeks the rabbits in the treatment group 2 and the control group 2 were sacrificed, and the expression of VEGF was detected in these rabbits. Results: The expression of VEGF was significantly enhanced in rabbits of the model group as compared with the normal control group (P<0.01), and gradually reduced with the lapse of time. The expression of VEGF in the control groups was significantly reduced as compared with the treatment

  7. Vascular smooth muscle cells for use in vascular tissue engineering obtained by endothelial-to-mesenchymal transdifferentiation (EnMT) on collagen matrices

    NARCIS (Netherlands)

    Krenning, Guido; Moonen, Jan-Renier A. J.; van Luyn, Marja J. A.; Harmsen, Martin C.

    2008-01-01

    The discovery of the endothelial progenitor cell (EPC) has led to an intensive research effort into progenitor cell-based tissue engineering of (small-diameter) blood vessels. Herein, EPC are differentiated to vascular endothelial cells and serve as the inner lining of bioartificial vessels. As yet,

  8. Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches

    Energy Technology Data Exchange (ETDEWEB)

    Baer, Caroline; Squadrito, Mario Leonardo [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Iruela-Arispe, M. Luisa, E-mail: arispe@mcdb.ucla.edu [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, University of California, Los Angeles 90095, CA (United States); De Palma, Michele, E-mail: michele.depalma@epfl.ch [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland)

    2013-07-01

    The ability of macrophages to promote vascular growth has been associated with the secretion and local delivery of classic proangiogenic factors (e.g., VEGF-A and proteases). More recently, a series of studies have also revealed that physical contact of macrophages with growing blood vessels coordinates vascular fusion of emerging sprouts. Interestingly, the interactions between macrophages and vascular endothelial cells (ECs) appear to be bidirectional, such that activated ECs also support the expansion and differentiation of proangiogenic macrophages from myeloid progenitors. Here, we discuss recent findings suggesting that dynamic angiogenic vascular niches might also exist in vivo, e.g. in tumors, where sprouting blood vessels and immature myeloid cells like monocytes engage in heterotypic interactions that are required for angiogenesis. Finally, we provide an account of emerging mechanisms of cell-to-cell communication that rely on secreted microvesicles, such as exosomes, which can offer a vehicle for the rapid exchange of molecules and genetic information between macrophages and ECs engaged in angiogenesis. -- Highlights: • Macrophages promote angiogenesis by secreting proangiogenic factors. • Macrophages modulate angiogenesis via cell-to-cell contacts with endothelial cells. • Endothelial cells promote the differentiation of proangiogenic macrophages. • Macrophages and endothelial cells may cooperate to form angiogenic vascular niches.

  9. Endothelial-mural cell signaling in vascular development and angiogenesis.

    Science.gov (United States)

    Gaengel, Konstantin; Genové, Guillem; Armulik, Annika; Betsholtz, Christer

    2009-05-01

    Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

  10. Effects of blood products on inflammatory response in endothelial cells in vitro.

    Directory of Open Access Journals (Sweden)

    Martin Urner

    Full Text Available BACKGROUND: Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. METHODS: The inflammatory response from pre-activated (endotoxin-stimulated and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC, platelet concentrates (PC and fresh frozen plasma (FFP was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. RESULTS: Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product-induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. CONCLUSION: Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells.

  11. he role of vascular endothelial growth factor in the pathogenesis of lichen planus and psoriasis

    OpenAIRE

    Artemina Е.М.; Shtoda U.М.; Slesarenko N.A.; Bakulev A.L.; Utz S.R.

    2014-01-01

    The goal: to investigate the process of angiogenesis by determining the level of vascular endothelial growth factor (VEGF) in the blood serum of patients with lichen planus (CPL) and psoriasis. Material and Methods. The study included 50 patients with CPL, 62 patients with psoriasis and 36 were in the control group of healthy individuals. All of the participants were to determine the level of VEGF in a blood serum before treatment. Results. Patients with CPL had an increase in the level of VE...

  12. Role of Copper and Vascular Endothelial Growth Factor (VEGF on Endometrial Angiogenesis

    Directory of Open Access Journals (Sweden)

    Yousef Rezaei Chianeh

    2013-07-01

    Full Text Available The formation of new blood vessels is the ini-tial step in neovascularisation. The first stagein angiogenesis is the activation of endothelialcells. Copper ions stimulate proliferation andimmigration of endothelial cells. It has beenshown that serum copper concentration in-creases as the cancer disease progresses andcorrelates with tumour incidence and burden.Copper ions also activate several proangiogenicfactors, e.g., vascular endothelial growth fac-tor, basic fibroblast growth factor, andinterleukin 1. This review concerns a brief in-troduction into the basics of blood vessel de-velopment as well as the regulatory mecha-nisms of this process. The role of copper ionsin angiogenesis is discussed.

  13. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.

    Science.gov (United States)

    Salmon, Andrew H J; Ferguson, Joanne K; Burford, James L; Gevorgyan, Haykanush; Nakano, Daisuke; Harper, Steven J; Bates, David O; Peti-Peterdi, Janos

    2012-08-01

    Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.

  14. Effect of ruthenium red, a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats.

    Science.gov (United States)

    Jain, Swati; Sharma, Bhupesh

    2016-10-01

    Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia by experimental diabetes. This study investigates the efficacy of a ruthenium red, a ryanodine receptor antagonist and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent vascular dementia in rats. Attentional set shifting and Morris water-maze test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of ruthenium red and pioglitazone has significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that ruthenium red, a ryanodine receptor antagonist and pioglitazone, a PPAR-γ agonist may be considered as potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent vascular dementia. Ryanodine receptor may be explored further for their possible benefits in vascular dementia.

  15. Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

    Science.gov (United States)

    Velez-Montoya, Raul; Clapp, Carmen; Rivera, Jose Carlos; Garcia-Aguirre, Gerardo; Morales-Cantón, Virgilio; Fromow-Guerra, Jans; Guerrero-Naranjo, Jose Luis; Quiroz-Mercado, Hugo

    2010-01-01

    Purpose: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity. Methods: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05. Results: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples. Conclusion: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group. PMID:20856587

  16. Synergism of matrix stiffness and vascular endothelial growth factor on mesenchymal stem cells for vascular endothelial regeneration.

    Science.gov (United States)

    Wingate, Kathryn; Floren, Michael; Tan, Yan; Tseng, Pi Ou Nancy; Tan, Wei

    2014-09-01

    Mesenchymal stem cells (MSCs) hold tremendous potential for vascular tissue regeneration. Research has demonstrated that individual factors in the cell microenvironment such as matrix elasticity and growth factors regulate MSC differentiation to vascular lineage. However, it is not well understood how matrix elasticity and growth factors combine to direct the MSC fate. This study examines the combined effects of matrix elasticity and vascular endothelial growth factor (VEGF) on both MSC differentiation into endothelial lineage and MSC paracrine signaling. MSCs were seeded in soft nanofibrous matrices with or without VEGF, and in Petri dishes with or without VEGF. Only MSCs seeded in three-dimensional soft matrices with VEGF showed significant increases in the expression of endothelial markers (vWF, eNOS, Flt-1, and Flk-1), while eliminating the expression of smooth muscle marker (SM-α-actin). MSCs cultured in VEGF alone on two-dimensional dishes showed increased expression of both early-stage endothelial and smooth muscle markers, indicating immature vascular differentiation. Furthermore, MSCs cultured in soft matrices with VEGF showed faster upregulation of endothelial markers compared with MSCs cultured in VEGF alone. Paracrine signaling studies found that endothelial cells cultured in the conditioned media from MSCs differentiated in the soft matrix and VEGF condition exhibited increased migration and formation of capillary-like structures. These results demonstrate that VEGF and soft matrix elasticity act synergistically to guide MSC differentiation into mature endothelial phenotype while enhancing paracrine signaling. Therefore, it is critical to control both mechanical and biochemical factors to safely regenerate vascular tissues with MSCs.

  17. Decreased expression of serum and microvascular vascular endothelial growth factor receptor-2 in meningococcal sepsis*.

    NARCIS (Netherlands)

    Flier, M. van der; Baerveldt, E.M.; Miedema, A.; Hartwig, N.G.; Hazelzet, J.A.; Emonts, M.; Groot, R. de; Prens, E.P.; Vught, A.J. van; Jansen, N.J.

    2013-01-01

    OBJECTIVES: To determine the skin microvessel expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels in children with meningococcal sepsis. DESIGN: Observational study. SETTING: Two tertiary academic children hospital PICUs.

  18. Vascular endothelial growth factor receptor-3 expression in mycosis fungoides

    DEFF Research Database (Denmark)

    Pedersen, Ida Holst; Willerslev-Olsen, Andreas; Vetter-Kauczok, Claudia;

    2012-01-01

    Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal...

  19. Vascular Endothelial Growth Factor, diagnostic and therapeutic aspects

    NARCIS (Netherlands)

    Kusumanto, Yoka Hadiani

    2006-01-01

    This thesis focuses on the diagnostic and therapeutic potential of Vascular Endothelial Growth Factor, an angiogenic growth factor. Since the recognition of VEGF’s pivotal role in physiological and pathological angiogenesis research has evolved from cell culture and animal experiments to application

  20. Effects of vascular endothelial growth factor on angiogenesis of the endothelial cells isolated from cavernous malformations

    Institute of Scientific and Technical Information of China (English)

    TAN YuZhen; ZHAO Yao; WANG HaiJie; ZHOU LiangFu; MAO Ying; LIU Rui; SHU Jia; WANG YongFei

    2008-01-01

    Human cerebral cavernous malformation (CM) is a common vascular malformation of the central nervous system. We have investigated the biological characteristics of CM endothelial cells and the cellular and molecular mechanisms of CM angiogenesis to offer new insights into exploring effective measures for treatment of this disease. The endothelial cells were isolated from CM tissue masses dissected during operation and expanded in vitro. Expression of VEGFR-1 and VEGFR-2 was examined with immunocytochemical staining. Proliferation, migration and tube formation of CM endothelial cells were determined using MTT, wounding and transmigration assays, and three-dimensional collagen type Ⅰ gel respectively. The endothelial cells were successfully isolated from the tissue specimens of 25 CMs dissected without dipolar electrocoagulation. The cells show the general characteristics of the vascular endothelial cells. Expression of VEGFR-1 and VEGFR-2 on the cells is higher than that on the normal cerebral microvascular endothelial cells. After treatment with VEGF, numbers of the proliferated and migrated cells, the maximal distance of cell migration and the length and area of capillary-like struc-tures formed in the three-dimensional collagen gel increase significantly. These results demonstrate that expression of VEGFR-1 and VEGFR-2 on CM endothelial cells is up-regulated. By binding to re-ceptors, VEGF may activate the downstream signaling pathways and promote proliferation, migration and tube formation of CM endothelial cells. VEGF/VEGFR signaling pathways play important regulating roles in CM angiogenesis.

  1. Cheiradone: a vascular endothelial cell growth factor receptor antagonist

    Directory of Open Access Journals (Sweden)

    Ahmed Nessar

    2008-01-01

    Full Text Available Abstract Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing and pathological conditions (tumour development. Vascular endothelial growth factor (VEGF, fibroblast growth factor-2 (FGF-2 and epidermal growth factor (EGF are the major angiogenic regulators. We have identified a natural product (cheiradone isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation and in vivo (the chick chorioallantoic membrane models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50 was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. Results Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20–7.50 μM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 μM respectively. Conclusion Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.

  2. In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability.

    Science.gov (United States)

    Yamauchi, Fumio; Kamioka, Yuji; Yano, Tetsuya; Matsuda, Michiyuki

    2016-09-15

    Vascular hyperpermeability is a pathological hallmark of cancer. Previous in vitro studies have elucidated roles of various signaling molecules in vascular hyperpermeability; however, the activities of such signaling molecules have not been examined in live tumor tissues for technical reasons. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we examined the activity of protein kinase A (PKA), which maintains endothelial barrier function. The level of PKA activity was significantly lower in the intratumoral endothelial cells than the subcutaneous endothelial cells. PKA activation with a cAMP analogue alleviated the tumor vascular hyperpermeability, suggesting that the low PKA activity in the endothelial cells may be responsible for the tumor-tissue hyperpermeability. Because the vascular endothelial growth factor (VEGF) receptor is a canonical inducer of vascular hyperpermeability and a molecular target of anticancer drugs, we examined the causality between VEGF receptor activity and the PKA activity. Motesanib, a kinase inhibitor for VEGF receptor, activated tumor endothelial PKA and reduced the vascular permeability in the tumor. Conversely, subcutaneous injection of VEGF decreased endothelial PKA activity and induced hyperpermeability of subcutaneous blood vessels. Notably, in cultured human umbilical vascular endothelial cells, VEGF activated PKA rather than decreasing its activity, highlighting the remarkable difference between its actions in vitro and in vivo These data suggested that the VEGF receptor signaling pathway increases vascular permeability, at least in part, by reducing endothelial PKA activity in the live tumor tissue. Cancer Res; 76(18); 5266-76. ©2016 AACR.

  3. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

    Directory of Open Access Journals (Sweden)

    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  4. Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

    Science.gov (United States)

    Sankrityayan, Himanshu; Majumdar, Anuradha S

    2016-01-01

    Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

  5. An in vitro method for evaluating vascular endothelial ADPase activity.

    Science.gov (United States)

    Caprino, L; Togna, A R; Stella, C; Togna, G

    1996-06-01

    Some xenobiotics, known to promote the development of thrombotic phenomena, affect vascular endothelium ADPase, a regulatory enzyme that inactivates vaso- and platelet-active adenine nucleotides. This proposed new experimental approach represents an improved method of evaluation of vascular endothelial ADPase activity which is assessed by measuring, at pre-established times, the degradation rate of exogenous ADP incubated with aortic bovine patches. The ADP dosage was performed by using a spectrophotometric enzymatic assay. Statistical analyses showed that the method is capable of highlighting the linearity of the ADPase activity time-course, thus indicating that the slopes of time-degradation curves of ADP are a valid index for this endothelial ectoenzyme activity. Results obtained with ADPase inhibiting or stimulating agent confirm that this in vitro method is an efficient tool for estimating the ability of xenobiotics or drugs to modify the nonthrombogenic properties of vascular endothelium.

  6. Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1/CD31): A Multifunctional Vascular Cell Adhesion Molecule.

    Science.gov (United States)

    Delisser, H M; Baldwin, H S; Albelda, S M

    1997-08-01

    PECAM-1/CD31 is a member of the immunoglobulin gene superfamily found on platelets, leukocytes, and endothelial cells, where it concentrates at cell-cell borders. It has been shown to both mediate cell-cell adhesion through homophilic and heterophilic interactions and to transduce intracellular signals that upregulate the function of integrins on leukocytes. Its cellular distribution and ability to mediate adhesive and signaling phenomena suggested that PECAM-1 was a multifunctional vascular cell adhesion molecule involved in leukocyte-endothelial and endothelial-endothelial interactions. These initial suggestions have been largely confirmed as recent studies have implicated PECAM-1 in the inflammatory process and in the formation of blood vessels. As our understanding of the molecular and functional properties of PECAM-1 grows, new insights will be gained that may have therapeutic implications for cardiovascular development and disease. (Trends Cardiovasc Med 1997;7:203-210). © 1997, Elsevier Science Inc.

  7. Viscoelastic properties of vascular endothelial cells exposed to uniaxial stretch

    Science.gov (United States)

    Osterday, Kathryn; Chew, Thomas; Loury, Phillip; Haga, Jason; Del Alamo, Juan C.; Chien, Shu

    2011-11-01

    Vascular endothelial cells (VECs) line the interior of blood vessels and regulate a variety of functions in the cardiovascular system. It is widely accepted that VECs will remodel themselves in response to mechanical stimuli, but few studies have analyzed the mechanical properties of these cells under stretch. We hypothesize that uniaxial stretch will cause an anisotropic realignment of actin filaments, and a change in the viscoelastic properties of the cell. To test this hypothesis, VECs were grown on a thin, transparent membrane mounted on a microscope. The membrane was stretched, consequently stretching the cells. Time-lapse sequences of the cells were taken every hour with a time resolution of 10 Hz. The random trajectories of intracellular endogenous particles were tracked using in-house algorithms. These trajectories were analyzed using a novel particle tracking microrheology formulation that takes into account the anisotropy of the cytoplasm of VECs. Supported by NSF CBET-1055697 CAREER Award (JCA) and NIH grants BRP HL064382 (SC), 1R01 HL080518 (SC).

  8. Improving hemocompatibility and accelerating endothelialization of vascular stents by a copper-titanium film.

    Science.gov (United States)

    Liu, Hengquan; Pan, Changjiang; Zhou, Shijie; Li, Junfeng; Huang, Nan; Dong, Lihua

    2016-12-01

    Bio-inorganic films and drug-eluting coatings are usually used to improve the hemocompatibility and inhibit restenosis of vascular stent; however, above bio-performances couldn't combine together with single materials. In the present study, we reported a simple approach to fabricate a metal film with the aim of imparting the stent with good blood compatibility and accelerating endothelialization. The films with various ratios of Cu and Ti were prepared through the physical vapor deposition. Phase structure and element composition were investigated by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), respectively. The releasing volume of copper ion in Cu/Ti film was determined by immersing test. The hemolysis ratio, platelet adhesion and clotting time were applied to evaluate the hemocompatibility. The proliferative behaviors of endothelial cells and smooth muscle cells under certain copper concentration were investigated in vitro and in vivo. Results indicated that copper-titanium films exhibited good hemocompatibility in vitro; however, the increase of Cu/Ti ratio could lead to increasing hemolysis ratio. Endothelial cells displayed more proliferative than smooth muscle cells when the copper concentration was film with low copper in vivo was observed at the 2nd week, indicating that the copper-titanium film with the lower copper concentration could promote endothelialization. Therefore, the inorganic copper-titanium film could be potential biomaterials to improve blood compatibility and accelerating endothelialization of vascular stents.

  9. Vascular progenitor cells isolated from human embryonic stem cells give rise to endothelial and smooth muscle like cells and form vascular networks in vivo.

    Science.gov (United States)

    Ferreira, Lino S; Gerecht, Sharon; Shieh, Hester F; Watson, Nicki; Rupnick, Maria A; Dallabrida, Susan M; Vunjak-Novakovic, Gordana; Langer, Robert

    2007-08-03

    We report that human embryonic stem cells contain a population of vascular progenitor cells that have the ability to differentiate into endothelial-like and smooth muscle (SM)-like cells. Vascular progenitor cells were isolated from EBs grown in suspension for 10 days and were characterized by expression of the endothelial/hematopoietic marker CD34 (CD34+ cells). When these cells are subsequently cultured in EGM-2 (endothelial growth medium) supplemented with vascular endothelial growth factor-165 (50 ng/mL), they give rise to endothelial-like cells characterized by a cobblestone cell morphology, expression of endothelial markers (platelet endothelial cell-adhesion molecule-1, CD34, KDR/Flk-1, vascular endothelial cadherin, von Willebrand factor), incorporation of acetylated low-density lipoprotein, and formation of capillary-like structures when placed in Matrigel. In contrast, when CD34+ cells are cultured in EGM-2 supplemented with platelet-derived growth factor-BB (50 ng/mL), they give rise to SM-like cells characterized by spindle-shape morphology, expression of SM cell markers (alpha-SM actin, SM myosin heavy chain, calponin, caldesmon, SM alpha-22), and the ability to contract and relax in response to common pharmacological agents such as carbachol and atropine but rarely form capillary-like structures when placed in Matrigel. Implantation studies in nude mice show that both cell types contribute to the formation of human microvasculature. Some microvessels contained mouse blood cells, which indicates functional integration with host vasculature. Therefore, the vascular progenitors isolated from human embryonic stem cells using methods established in the present study could provide a means to examine the mechanisms of endothelial and SM cell development, and they could also provide a potential source of cells for vascular tissue engineering.

  10. Effects of Angiotensin Ⅱ on Vascular Endothelial Growth Factor Expression in Early Endothelial Progenitor Cells from Human Peripheral Blood%血管紧张素Ⅱ对外周血早期内皮祖细胞血管内皮生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    孙文文; 任国庆; 汪奕斌; 张浩

    2011-01-01

    Aim To investigate the effect of angiotensin Ⅱ on vascular endothelial growth factor expression of early endothelial progenitor cells. Methods Total mononuclear cells (MNCs) were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. After 7 days of culture, several groups of attached cells were incubated with angiotensin Ⅱ (to make a series of concentrations: 10-3 mol/L, 10 -5 mol/L, 10-7 mol/L vehicle control for 24 h), angiotensin Ⅱ + valsartan, angiotensin Ⅱ + PD123319. The cells were observed under inverted microscope, and characterized as adherent cells double positive for DiL DL-uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope. The early endothelial progenitor cells were further documented by demonstrating the expression of cell markers with flow cytometry. Enzyme-linked immunospecific assay (ELISA) were used to assess vascular endothelial growth factor expression. Results Our data indicated that angiotensin Ⅱ can significantly increase the vascular endothelial growth factor expression, with a maximum at 10-3 mol/L after 24 hours (P <0. 05); These effects can be attenuated by pre-treatment with valsartan but not PD123319.Conclusion It is suggested that angiotensin Ⅱ induces vascular endothelial growth factor protein secretion via the angiotensin Ⅱ receptor-1 but not angiotensin Ⅱ receptor-2.%目的 观察血管紧张素Ⅱ对外周血早期内皮祖细胞血管内皮生长因子表达的影响.方法 密度梯度离心法获取外周血单个核细胞,培养7天,收集贴壁细胞,随机分对照组、血管紧张素Ⅱ各浓度 (10-3 mol/L、10-5 mol/L、10-7 mol/L) 组、血管紧张素Ⅱ+缬沙坦组、血管紧张素Ⅱ+ PD123319组.多波长激光共聚焦显微镜鉴定FITC标记荆豆凝集素Ⅰ和 DiI标记的乙酰化低密度脂蛋白双染色阳性为早期内皮祖细胞,流式细胞仪

  11. Arachidonic metabolism and radiation toxicity in cultures of vascular endothelial cells

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    Eldor, A.; Vlodavsky, I.; Fuks, Z.; Matzner, Y.; Rubin, D.B. (Hadassah Univ. Hospital, Jerusalem (Israel) Rush-Presbyterian-St. Luke' s Medical Center, Chicago, IL (USA))

    1989-06-01

    The authors conclude that the observed changes in eicosanoid production by vascular endothelial cells exposed to ionizing irradiation may be relevant to the pathogenesis of post-radiation injury in small and large blood vessels. Anomalies of PGI{sub 2} production may lead to thrombosis and accelerated arteriosclerosis which are observed in irradiated vessels. The generation of potent cells may greatly facilitate inflammation in irradiated vessels. The model of irradiated cultured endothelial cells may also be useful for the study of various methods and agents aimed at reducing the radiation induced damage to blood vessels. Evaluation of the capacity of cultured endothelial cells to produce eicosanoids may serve as an appropriate index for the metabolic damage induced by radiation. (author).

  12. Sodium renders endothelial cells sticky for red blood cells

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    Hans eOberleithner

    2015-06-01

    Full Text Available Negative charges in the glycocalyx of red blood cells (RBC and vascular endothelial cells (EC facilitate frictionless blood flow through blood vessels. Na+ selectively shields these charges controlling surface electronegativity. The question was addressed whether the ambient Na+ concentration controls RBC-EC interaction. Using atomic force microscopy (AFM adhesion forces between RBC and endothelial glycocalyx were quantified. A single RBC, mounted on an AFM cantilever, was brought in physical contact with the endothelial surface and then pulled off. Adhesion forces were quantified (i after enzymatic removal of negative charges in the glycocalyx, (ii under different ambient Na+ and (iii after applying the intracellular aldosterone receptor antagonist spironolactone. Removal of negative surface charges increases RBC-EC interaction forces. A stepwise increase of ambient Na+ from 133 to 140 mM does not affect them. However, beyond 140 mM Na+ adhesion forces increase sharply (10% increase of adhesion force per 1 mM increase of Na+. Spironolactone prevents this response. It is concluded that negative charges reduce adhesion between RBC and EC. Ambient Na+ concentration determines the availability of free negative charges. Na+ concentrations in the low physiological range (below 140 mM allow sufficient amounts of vacant negative charges so that adhesion of RBC to the endothelial surface is small. In contrast, Na+ in the high physiological range (beyond 140 mM saturates the remaining negative surface charges thus increasing adhesion. Aldosterone receptor blockade by spironolactone prevents Na+ induced RBC adhesion to the endothelial glycocalyx. Extrapolation of in vitro experiments to in vivo conditions leads to the hypothesis that high sodium intake is likely to increase the incidence of thrombotic events.

  13. Sodium renders endothelial cells sticky for red blood cells.

    Science.gov (United States)

    Oberleithner, Hans; Wälte, Mike; Kusche-Vihrog, Kristina

    2015-01-01

    Negative charges in the glycocalyx of red blood cells (RBC) and vascular endothelial cells (EC) facilitate frictionless blood flow through blood vessels. Na(+) selectively shields these charges controlling surface electronegativity. The question was addressed whether the ambient Na(+) concentration controls RBC-EC interaction. Using atomic force microscopy (AFM) adhesion forces between RBC and endothelial glycocalyx were quantified. A single RBC, mounted on an AFM cantilever, was brought in physical contact with the endothelial surface and then pulled off. Adhesion forces were quantified (i) after enzymatic removal of negative charges in the glycocalyx, (ii) under different ambient Na(+) and (iii) after applying the intracellular aldosterone receptor antagonist spironolactone. Removal of negative surface charges increases RBC-EC interaction forces. A stepwise increase of ambient Na(+) from 133 to 140 mM does not affect them. However, beyond 140 mM Na(+) adhesion forces increase sharply (10% increase of adhesion force per 1 mM increase of Na(+)). Spironolactone prevents this response. It is concluded that negative charges reduce adhesion between RBC and EC. Ambient Na(+) concentration determines the availability of free negative charges. Na(+) concentrations in the low physiological range (below 140 mM) allow sufficient amounts of vacant negative charges so that adhesion of RBC to the endothelial surface is small. In contrast, Na(+) in the high physiological range (beyond 140 mM) saturates the remaining negative surface charges thus increasing adhesion. Aldosterone receptor blockade by spironolactone prevents Na(+) induced RBC adhesion to the endothelial glycocalyx. Extrapolation of in vitro experiments to in vivo conditions leads to the hypothesis that high sodium intake is likely to increase the incidence of thrombotic events.

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

    Energy Technology Data Exchange (ETDEWEB)

    Latham, Antony M.; Odell, Adam F. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Mughal, Nadeem A. [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Issitt, Theo; Ulyatt, Clare; Walker, John H. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Homer-Vanniasinkam, Shervanthi [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)

    2012-11-01

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

  15. Characterization of vascular endothelial progenitor cells from chicken bone marrow

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    Bai Chunyu

    2012-05-01

    Full Text Available Abstract Background Endothelial progenitor cells (EPC are a type of stem cell used in the treatment of atherosclerosis, vascular injury and regeneration. At present, most of the EPCs studied are from human and mouse, whereas the study of poultry-derived EPCs has rarely been reported. In the present study, chicken bone marrow-derived EPCs were isolated and studied at the cellular level using immunofluorescence and RT-PCR. Results We found that the majority of chicken EPCs were spindle shaped. The growth-curves of chicken EPCs at passages (P 1, -5 and -9 were typically “S”-shaped. The viability of chicken EPCs, before and after cryopreservation was 92.2% and 81.1%, respectively. Thus, cryopreservation had no obvious effects on the viability of chicken EPCs. Dil-ac-LDL and FITC-UAE-1 uptake assays and immunofluorescent detection of the cell surface markers CD34, CD133, VEGFR-2 confirmed that the cells obtained in vitro were EPCs. Observation of endothelial-specific Weibel-Palade bodies using transmission electron microscopy further confirmed that the cells were of endothelial lineage. In addition, chicken EPCs differentiated into endothelial cells and smooth muscle cells upon induction with VEGF and PDGF-BB, respectively, suggesting that the chicken EPCs retained multipotency in vitro. Conclusions These results suggest that chicken EPCs not only have strong self-renewal capacity, but also the potential to differentiate into endothelial and smooth muscle cells. This research provides theoretical basis and experimental evidence for potential therapeutic application of endothelial progenitor cells in the treatment of atherosclerosis, vascular injury and diabetic complications.

  16. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: relation to prognosis

    DEFF Research Database (Denmark)

    Bonnesen, Barbara; Pappot, Helle; Holmstav, Julie;

    2009-01-01

    elements in neoplastic cells and their microenvironment have recently been and are continuously developed including drugs inhibiting the angiogenic system. Angiogenic factor vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) seem to play key...

  17. Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.

    Science.gov (United States)

    Oltean, Sebastian; Qiu, Yan; Ferguson, Joanne K; Stevens, Megan; Neal, Chris; Russell, Amy; Kaura, Amit; Arkill, Kenton P; Harris, Kirstie; Symonds, Clare; Lacey, Katja; Wijeyaratne, Lihini; Gammons, Melissa; Wylie, Emma; Hulse, Richard P; Alsop, Chloe; Cope, George; Damodaran, Gopinath; Betteridge, Kai B; Ramnath, Raina; Satchell, Simon C; Foster, Rebecca R; Ballmer-Hofer, Kurt; Donaldson, Lucy F; Barratt, Jonathan; Baelde, Hans J; Harper, Steven J; Bates, David O; Salmon, Andrew H J

    2015-08-01

    Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

  18. Healing arterial ulcers: Endothelial lining regeneration upon vascular denudation injury.

    Science.gov (United States)

    McDonald, Austin I; Iruela-Arispe, M Luisa

    2015-09-01

    Thrombosis and restenosis are the most prevalent late complications of coronary artery stenting. Current standards of clinical care focus on prevention of smooth muscle cell proliferation by the use of drug-eluting stents able to release anti-proliferative drugs. Unfortunately, these drugs also block endothelial cell proliferation and, in this manner, prevent recovery of endothelial cell coverage. Continued lack of endothelial repair leaves the root cause of thrombosis and restenosis unchanged, creating a vicious cycle where drug-mediated prevention of restenosis simultaneously implies promotion of thrombosis. In this issue of Vascular Pharmacology, Hussner and colleagues provide in vitro evidence and a mechanistic basis for the use of atorvastatin in stents as a way to bypass this roadblock. Here we review the pathological mechanisms and therapeutic approaches to restore flow in occluded arteries. We argue that rational design of drug eluting stents should focus on specific inhibition of smooth muscle cell proliferation with concurrent stimulation of endothelial regeneration. We comment on the current poor understanding of the cellular and molecular regulation of endothelial cell proliferation in the context of a functional artery, and on the pitfalls of extrapolating from the well-studied process of neovascularization by sprouting vessel formation.

  19. Vascular endothelial growth factor (VEGF and prostate pathology

    Directory of Open Access Journals (Sweden)

    Francisco Botelho

    2010-08-01

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

  20. Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling.

    Science.gov (United States)

    Wilson, Christopher W; Ye, Weilan

    2014-01-01

    The ability of blood vessels to sense and respond to stimuli such as fluid flow, shear stress, and trafficking of immune cells is critical to the proper function of the vascular system. Endothelial cells constantly remodel their cell-cell junctions and the underlying cytoskeletal network in response to these exogenous signals. This remodeling, which depends on regulation of the linkage between actin and integral junction proteins, is controlled by a complex signaling network consisting of small G proteins and their various downstream effectors. In this commentary, we summarize recent developments in understanding the small G protein RAP1 and its effector RASIP1 as critical mediators of endothelial junction stabilization, and the relationship between RAP1 effectors and modulation of different subsets of endothelial junctions.   The vasculature is a dynamic organ that is constantly exposed to a variety of signaling stimuli and mechanical stresses. In embryogenesis, nascent blood vessels form via a process termed vasculogenesis, wherein mesodermally derived endothelial precursor cells aggregate into cords, which subsequently form a lumen that permits trafficking of plasma and erythrocytes. (1)(,) (2) Angiogenesis occurs after establishment of this primitive vascular network, where new vessels sprout from existing vessels, migrate into newly expanded tissues, and anastomose to form a functional and complex circulatory network. (1)(,) (2) In the mouse, this process occurs through the second half of embryogenesis and into postnatal development in some tissues, such as the developing retinal vasculature. (3) Further, angiogenesis occurs in a variety of pathological conditions, such as diabetic retinopathy, age-related macular degeneration, inflammatory diseases such as rheumatoid arthritis, wound healing, and tumor growth. (1)(,) (2)(,) (4) Both vasculogenesis and angiogenesis are driven through signaling by vascular endothelial growth factor (VEGF), and therapeutic

  1. Effect of agmatine on experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Nader, M A; Gamiel, N M; El-Kashef, H; Zaghloul, M S

    2016-05-01

    This study was designed to investigate the effect of agmatine sulfate (AG, CAS2482-00-0) in nicotine (NIC)-induced vascular endothelial dysfunction (VED) in rabbits. NIC was administered to produce VED in rabbits with or without AG for 6 weeks. Serum lipid profile, serum thiobarbituric acid reactive substances, reduced glutathione, superoxide dismutase generation, serum nitrite/nitrate, serum vascular cellular adhesion molecule-1 (VCAM-1), and aortic nuclear factor κB (NF-κB) levels were analyzed.Treatment with AG markedly improves lipid profile and prevented NIC-induced VED and oxidative stress. The mechanism of AG in improving NIC-induced VED may be due to the significant reduction in serum VCAM-1 levels and aortic NF-κB. Thus, it may be concluded that AG reduces the oxidative stress, nitric oxide production, VCAM-1 levels, and aortic NF-κB expression, thereby consequently improving the integrity of vascular endothelium.

  2. 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.

  3. Opioid-induced proliferation of vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Sandra Leo

    2009-05-01

    Full Text Available Sandra Leo1,2, Rony Nuydens1, Theo F Meert11Pain and Neurology, CNS Department, Johnson and Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium; 2Laboratory of Biological Psychology, University of Leuven, Leuven, BelgiumAbstract: Angiogenesis is an important issue in cancer research and opioids are often used to treat pain in cancer patients. Therefore it is important to know if the use of opioids is associated with an aberrant stimulation of tumor growth triggered by the stimulation of angiogenesis in cancer patients. Some studies in the literature have suggested the presence of the μ3 opioid receptor, known as the receptor for many opioids, on endothelial cells, which are key players in the process of angiogenesis. In this study we used endothelial cells known to express the μ3 opioid receptor (MOR3, to evaluate the effects of morphine on angiogenesis. We first investigated the effect of morphine on the proliferation of endothelial cells. We showed that morphine is able to stimulate vascular endothelial cell proliferation in vitro. This effect of morphine is mediated by the mitogen-activated protein kinase (MAPK pathway as pre-treatment with PD98059 inhibited this excessive proliferation. Because previous studies indicated nitric oxide (NO as a downstream messenger we investigated the role of NO in the aberrant proliferation of endothelial cells. Our data could not confirm these findings using intracellular NO measurements and quantitative fluorescence microscopy. The potential use and pitfalls of opioids in cancer patients is discussed in light of these negative findings. Keywords: endothelial cells, morphine, cell proliferation, MAPK, nitric oxide, μ3 opioid receptor, angiogenesis

  4. Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation.

    Science.gov (United States)

    Roth, Lise; Prahst, Claudia; Ruckdeschel, Tina; Savant, Soniya; Weström, Simone; Fantin, Alessandro; Riedel, Maria; Héroult, Mélanie; Ruhrberg, Christiana; Augustin, Hellmut G

    2016-04-26

    Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.

  5. Local Augmented Angiotensinogen Secreted from Apoptotic Vascular Endothelial Cells Is a Vital Mediator of Vascular Remodelling.

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    Shyh-Jong Wu

    Full Text Available Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs and vascular smooth muscle cells (VSMCs through serum starvation (SS. After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II were found in a serum-free medium conditioned by HUVECs (SSC. The increased Ang II was suppressed using lisinopril (an ACE inhibitor treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

  6. Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Jianbo He

    2015-01-01

    Full Text Available Diabetic retinopathy (DR is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1 blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ treatment or Insulin2 gene mutation (Akita in mice. Protein expression and localization were examined by western blots (WB and immunofluorescence (IF. mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [3H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC adhesion (or retinal leukostasis, expression of intercellular adhesion molecule- (ICAM- 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO- 1, and the cell adhesion protein vascular endothelial (VE cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR.

  7. Expression of vascular endothelial growth factor in malignant mesothelioma.

    Science.gov (United States)

    Aoe, Keisuke; Hiraki, Akio; Tanaka, Takehiro; Gemba, Ken-Ichi; Taguchi, Koji; Murakami, Tomoyuki; Sueoka, Naoko; Kamei, Toshiaki; Ueoka, Hiroshi; Sugi, Kazuro; Yoshino, Tadashi; Kishimoto, Takumi

    2006-01-01

    Malignant mesothelioma is the most common primary pleural neoplasm. Angiogenesis is an important component of a variety of pathological processes, including carcinogenesis and tumor metastases. Vascular endothelial growth factor (VEGF) is the most potent known endothelial, cell specific mitogen. The authors assessed the relation between VEGF expression and clinicopathological variables or overall survival, in malignant mesothelioma. We studied 37 patients with malignant pleural mesothelioma and found that 36 out of 37 (97.3%) malignant mesothelioma samples were stained positively for VEGF. An increased expression of VEGF was observed in the epithelioid type compared with the other histological types of malignant mesothelioma, including the biphasic and sarcomatoid types. No statistically significant association was observed between VEGF expression and gender, age, or clinical stage. Furthermore, the expression of VEGF did not impact on the survival of patients with malignant mesothelioma. Although VEGF expression might be important for tumor development and maintenance, it was not identified as a prognostic factor in malignant mesothelioma.

  8. Involvement of Rho-kinase in experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Shah, Dhvanit I; Singh, Manjeet

    2006-02-01

    The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy) induced vascular endothelial dysfunction (VED). Streptozotocin (55 mg kg(-1), i.v., once only) and methionine (1.7% w/w, p.o., daily for 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM) respectively. VED was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) concentration was estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard agent to improve vascular endothelial dysfunction. Fasudil (15 mg kg(-1) and 30 mg kg(-1), p.o., daily) and atorvastatin (30 mg kg(-1), p.o., daily) treatments significantly attenuated increase in serum glucose and homocysteine but their concentrations remained markedly higher than sham control value. Fasudil and atorvastatin treatments markedly prevented DM and HHcy-induced (i) attenuation of acetylcholine induced endothelium-dependent relaxation, (ii) impairment of vascular endothelial lining, (iii) decrease in serum nitrite/nitrate concentration, and (iv) increase in serum TBARS. It may be concluded that fasudil prevented DM and HHcy-induced VED partially by decreasing serum glucose and homocysteine concentration due to inhibition of Rho-kinase. Moreover, inhibition of Rho-kinase by fasudil and consequent prevention of oxidative stress may have directly improved VED in diabetic and hyperhomocysteinemic rats. The Rho-kinase appears to be a pivotal target site involved in DM and HHcy-induced VED.

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

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    Ekatherina Stoyanova

    Full Text Available AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

  10. Resveratrol Treatment Normalizes the Endothelial Function and Blood Pressure in Ovariectomized Rats

    Science.gov (United States)

    Fabricio, Victor; Oishi, Jorge Camargo; Biffe, Bruna Gabriele; Ruffoni, Leandro Dias Gonçalves; da Silva, Karina Ana; Nonaka, Keico Okino; Rodrigues, Gerson Jhonatan

    2017-01-01

    Background Despite knowing that resveratrol has effects on blood vessels, blood pressure and that phytostrogens can also improve the endothelium-dependent relaxation/vasodilation, there are no reports of reveratrol's direct effect on the endothelial function and blood pressure of animals with estrogen deficit (mimicking post-menopausal increased blood pressure). Objective To verify the effect of two different periods of preventive treatment with resveratrol on blood pressure and endothelial function in ovariectomized young adult rats. Methods 3-month old female Wistar rats were used and distributed in 6 groups: intact groups with 60 or 90 days, ovariectomized groups with 60 or 90 days, and ovariectomized treated with resveratrol (10 mg/kg of body weight per day) for 60 or 90 days. The number of days in each group corresponds to the duration of the experimental period. Vascular reactivity study was performed in abdominal aortic rings, systolic blood pressure was measured and serum nitric oxide (NO) concentration was quantified. Results Ovariectomy induced blood pressure increase 60 and 90 days after surgery, whereas the endothelial function decreased only 90 days after surgery, with no difference in NO concentration among the groups. Only longer treatment (90 days) with resveratrol was able to improve the endothelial function and normalize blood pressure. Conclusion Our results suggest that 90 days of treatment with resveratrol is able to improve the endothelial function and decrease blood pressure in ovariectomized rats.

  11. Mesoporous bioactive glass scaffolds for efficient delivery of vascular endothelial growth factor.

    Science.gov (United States)

    Wu, Chengtie; Fan, Wei; Chang, Jiang; Xiao, Yin

    2013-09-01

    In this article, we, for the first time, investigated mesoporous bioactive glass scaffolds for the delivery of vascular endothelial growth factor. We have found that mesoporous bioactive glass scaffolds have significantly higher loading efficiency and more sustained release of vascular endothelial growth factor than non-mesoporous bioactive glass scaffolds. In addition, vascular endothelial growth factor delivery from mesoporous bioactive glass scaffolds has improved the viability of endothelial cells. The study has suggested that mesopore structures in mesoporous bioactive glass scaffolds play an important role in improving the loading efficiency, decreasing the burst release, and maintaining the bioactivity of vascular endothelial growth factor, indicating that mesoporous bioactive glass scaffolds are an excellent carrier of vascular endothelial growth factor for potential bone tissue engineering applications.

  12. SNS-032 Prevents Tumor Cell-Induced Angiogenesis By Inhibiting Vascular Endothelial Growth Factor

    Directory of Open Access Journals (Sweden)

    M. Aktar Ali

    2007-05-01

    Full Text Available Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs and human glioblastoma cells (U87MG. SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle. In this study, we examined the proliferation and viability of HUVECs and U87MG cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 inhibited threedimensional capillary network formations of endothelial cells. In a coculture study, SNS-032 completely prevented U87MG cell-mediated capillary formation of HUVECs. This inhibitor also prevented the migration of HUVECs when cultured alone or cocultured with U87MG cells. In addition, SNS-032 significantly prevented the production of vascular endothelial growth factor (VEGF in both cell lines, whereas SNS-032 was less effective in preventing capillary network formation and migration of endothelial cells when an active recombinant VEGF was added to the medium. In conclusion, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF.

  13. Acute exercise improves endothelial function despite increasing vascular resistance during stress in smokers and nonsmokers.

    Science.gov (United States)

    Rooks, Cherie R; McCully, Kevin K; Dishman, Rod K

    2011-09-01

    The present study examined the effect of acute exercise on flow mediated dilation (FMD) and reactivity to neurovascular challenges among female smokers and nonsmokers. FMD was determined by arterial diameter, velocity, and blood flow measured by Doppler ultrasonography after forearm occlusion. Those measures and blood pressure and heart rate were also assessed in response to forehead cold and the Stroop Color-Word Conflict Test (CWT) before and after 30 min of rest or an acute bout of cycling exercise (∼50% VO₂ peak). Baseline FMD and stress responses were not different between smokers and nonsmokers. Compared to passive rest, exercise increased FMD and decreased arterial velocity and blood flow responses during the Stroop CWT and forehead cold in both groups. Overall, acute exercise improved endothelial function among smokers and nonsmokers despite increasing vascular resistance and reducing limb blood flow during neurovascular stress.

  14. Genetic analysis of blood vessel formation role of endothelial versus smooth muscle cells.

    Science.gov (United States)

    Carmeliet, P; Collen, D

    1997-11-01

    Formation of new blood vessels is vital during embryogenesis, essential for reproduction and wound healing during adulthood, and required to rescue tissue during ischemia. Neovascularization may, however, also contribute to the pathogenesis of several disorders, including tumorigenesis, diabetic vasculopathy, and chronic inflammation. Initially, blood vessels form as endothelium-lined channels by in situ differentiation of endothelial cells. Subsequently, they sprout and remodel into a highly organized and interconnected vascular network. During further maturation of the blood vessels, a sheet of primitive vascular smooth muscle cells surrounds the endothelium-lined channels, which controls endothelial cell function and provides structural support. Recent molecular analyses have identified candidate molecules that affect these processes. Their in vivo role has been further established by targeted gene manipulation in transgenic mice. This review highlights recent developments in the genetic analysis of blood vessel formation, as deduced from analysis of gene-inactivated mice. (Trends Cardiovasc Med 1997;7:271-281). © 1997, Elsevier Science Inc.

  15. Interaction between human monocytes and vascular smooth muscle cells induces vascular endothelial growth factor expression.

    Science.gov (United States)

    Hojo, Y; Ikeda, U; Maeda, Y; Takahashi, M; Takizawa, T; Okada, M; Funayama, H; Shimada, K

    2000-05-01

    The objective of this study was to investigate whether synthesis of vascular endothelial growth factor (VEGF), a major mitogen for vascular endothelial cells, was induced by a cell-to-cell interaction between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cell) were cocultured. VEGF levels in the coculture medium were determined by enzyme-linked immunosorbent assay. Northern blot analysis of VEGF mRNA was performed using a specific cDNA probe. Immunohistochemistry was performed to determine which types of cell produce VEGF. Adding THP-1 cells to VSMCs for 24 h increased VEGF levels of the culture media, 8- and 10-fold relative to those of THP-1 cells and VSMCs alone, respectively. Northern blot analysis showed that VEGF mRNA expression was induced in the cocultured cells and peaked after 12 h. Immunohistochemistry disclosed that both types of cell in the coculture produced VEGF. Separate coculture experiments revealed that both direct contact and a soluble factor(s) contributed to VEGF production. Neutralizing anti-interleukin (IL)-6 antibody inhibited VEGF production by the coculture of THP-1 cells and VSMCs. A cell-to-cell interaction between monocytes and VSMCs induced VEGF synthesis in both types of cell. An IL-6 mediated mechanism is at least partially involved in VEGF production by the cocultures. Local VEGF production induced by a monocyte-VSMC interaction may play an important role in atherosclerosis and vascular remodeling.

  16. Red blood cells in retinal vascular disorders.

    Science.gov (United States)

    Agrawal, Rupesh; Sherwood, Joseph; Chhablani, Jay; Ricchariya, Ashutosh; Kim, Sangho; Jones, Philip H; Balabani, Stavroula; Shima, David

    2016-01-01

    Microvascular circulation plays a vital role in regulating physiological functions, such as vascular resistance, and maintaining organ health. Pathologies such as hypertension, diabetes, or hematologic diseases affect the microcirculation posing a significant risk to human health. The retinal vasculature provides a unique window for non-invasive visualisation of the human circulation in vivo and retinal vascular image analysis has been established to predict the development of both clinical and subclinical cardiovascular, metabolic, renal and retinal disease in epidemiologic studies. Blood viscosity which was otherwise thought to play a negligible role in determining blood flow based on Poiseuille's law up to the 1970s has now been shown to play an equally if not a more important role in controlling microcirculation and quantifying blood flow. Understanding the hemodynamics/rheology of the microcirculation and its changes in diseased states remains a challenging task; this is due to the particulate nature of blood, the mechanical properties of the cells (such as deformability and aggregability) and the complex architecture of the microvasculature. In our review, we have tried to postulate a possible role of red blood cell (RBC) biomechanical properties and laid down future framework for research related to hemorrheological aspects of blood in patients with retinal vascular disorders.

  17. Effects of Salvia miltiorrhiza on Hemorheology and vascular endothelial function in patients with unstable angina pectoris

    Institute of Scientific and Technical Information of China (English)

    Shi-Lian Chen; Sheng-Bing Huang

    2016-01-01

    Objective:To investigate the effect of Salvia miltiorrhiza (SM) on vascular endothelial function and hemorheology in patients with unstable angina pectoris (UAP).Methods: A total of 60 cases of UAP patients from October 2014 to October 2015 as the research object, randomly divided into treatment group and control group; the two groups were treated with conventional bed rest, ECG monitoring, oxygen inhalation, application of nitroglycerin, beta blockers, aspirin and antiplatelet, statin therapy, the treatment group based on the use of salvianolate 200 mg+5% glucose 250 mL (neutralization amount of 0.9% sodium chloride was used in patients with diabetes or glucose insulin) intravenous drip, 1 times/d, two groups were treated for 2 weeks; the two groups before and after treatment and take venous blood in the morning fasting peripheral blood viscosity, plasma viscosity, measured by automatic blood rheometer (low and middle shear and high shear rate), hematocrit and erythrocyte aggregation index, serum endothelin (ET) and nitric oxide (NO) level was measured by nitrate reductase Set.Results:after the treatment, the treatment group, the plasma viscosity, whole blood viscosity (low shear, cut and high shear rate), red blood cell hematocrit and red blood cell aggregation index decreased than the control group, there is statistical significance; after treatment, in treatment group, the serum NO level, et reduce degree is significantly better than the contrast group, there is statistical significance.Conclusion: Salvia miltiorrhiza can effectively improve blood rheology, improve microcirculation, regulate vascular endothelial function, effectively reduce the risk of cardiovascular events in UAP patients, it is worthy of clinical application.

  18. Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults.

    Science.gov (United States)

    Jokura, Hiroko; Watanabe, Isamu; Umeda, Mika; Hase, Tadashi; Shimotoyodome, Akira

    2015-10-01

    Epidemiological studies indicate that habitual coffee consumption lowers the risk of diabetes and cardiovascular diseases. Postprandial hyperglycemia is a direct and independent risk factor for cardiovascular diseases. We previously demonstrated that coffee polyphenol ingestion increased secretion of Glucagon-like peptide 1 (GLP-1), which has been shown to exhibit anti-diabetic and cardiovascular effects. We hypothesized coffee polyphenol consumption may improve postprandial hyperglycemia and vascular endothelial function by increasing GLP-1 release and/or reducing oxidative stress. To examine this hypothesis, we conducted a randomized, acute, crossover, intervention study in healthy male adults, measuring blood parameters and flow-mediated dilation (FMD) after ingestion of a meal with or without coffee polyphenol extract (CPE). Nineteen subjects consumed a test meal with either a placebo- or CPE-containing beverage. Blood biomarkers and FMD were measured at fasting and up to 180 minutes postprandially. The CPE beverage led to a significantly lower peak postprandial increase in blood glucose and diacron-reactive oxygen metabolite, and significantly higher postprandial FMD than the placebo beverage. Postprandial blood GLP-1 increase tended to be higher after ingestion of the CPE beverage, compared with placebo. Subclass analysis revealed that the CPE beverage significantly improved postprandial blood GLP-1 response and reduced blood glucose increase in the subjects with a lower insulinogenic index. Correlation analysis showed postprandial FMD was negatively associated with blood glucose increase after ingestion of the CPE beverage. In conclusion, these results suggest that coffee polyphenol consumption improves postprandial hyperglycemia and vascular endothelial function, which is associated with increased GLP-1 secretion and decreased oxidative stress in healthy humans.

  19. Update on vascular endothelial Ca(2+) signalling: A tale of ion channels, pumps and transporters.

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-07-26

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca(2+) signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca(2+) levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca(2+) signals, ranging from brief, localized Ca(2+) pulses to prolonged Ca(2+) oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca(2+) signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca(2+) releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca(2+) removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca(2+) machinery in vascular ECs under both physiological and pathological conditions.

  20. Endothelial progenitor cell differentiation using cryopreserved, umbilical cord blood-derived mononuclear cells

    Institute of Scientific and Technical Information of China (English)

    Jun-ho JANG; Hugh C KIM; Sun-kyung KIM; Jeong-eun CHOI; Young-jin KIM; Hyun-woo LEE; Seok-yun KANG; Joon-seong PARK; Jin-hyuk CHOI; Ho-yeong LIM

    2007-01-01

    Aim: To investigate the endothelial differentiation potentiality of umbilical cord blood (UCB), we induced the differentiation of endothelial progenitor cells (EPC)from cryopreserved UCB-derived mononuclear cells (MNC). Methods: MNC from cryopreserved UCB and peripheral blood (PB) were cultured in M199 medium with endothelial cell growth supplements for 14 d. EPC were characterized by RT-PCR,flow cytometry, and immunocytochemistry analysis. The proliferation of differen-tiated EPC was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTI') assay, and vascular endothelial growth factor (VEGF) concentra-tion was measured using an ELISA kit. Characteristics of UCB-derived EPC were compared with those of PB-derived EPC. Results: A number of round-shaped cells were loosely attached to the bottom after 24 h culture, and numerous spindle-shaped cells began to appear from the round-shaped ones on d 7. Those cells expressed endothelial markers such as, Fit-1/VEGFR-1, ecNOS, VE-cadherin, yon Willebrand factor, and secreted VEGF. The patterns of endothelial markers of EPC from PB and UCB did not show striking differences. The results of the prolifera-tion and secretion of VEGF were also similar. Conclusion: We successfully cul-tured UCB cells stored at -196 ℃ into cells with the quality of endothelial cells.Those EPC could be used for angiogenic therapeutics by activating adjacent endothelial cells and enhancing angiogenesis.

  1. Endothelial and vascular dysfunctions and insulin resistance in rats fed a high-fat, high-sucrose diet.

    Science.gov (United States)

    Bourgoin, Frédéric; Bachelard, Hélène; Badeau, Mylène; Mélançon, Sébastien; Pitre, Maryse; Larivière, Richard; Nadeau, André

    2008-09-01

    This study was designed to examine the effects of a high-fat, high-sucrose (HFHS) diet on vascular and metabolic actions of insulin. Male rats were randomized to receive an HFHS or regular chow diet for 4 wk. In a first series of experiments, the rats had pulsed Doppler flow probes and intravascular catheters implanted to measure blood pressure, heart rate, and regional blood flows. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine skeletal muscle glucose transport activity and to determine in vitro vascular reactivity, endothelial nitric oxide synthase (eNOS) protein expression in muscle and vascular tissues and endothelin content, nitrotyrosine formation, and NAD(P)H oxidase protein expression in vascular tissues. The HFHS-fed rats displayed insulin resistance, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, elevated blood pressure, and impaired insulin-mediated renal and skeletal muscle vasodilator responses. A reduction in endothelium-dependent vasorelaxation, accompanied by a decreased eNOS protein expression in muscles and blood vessel endothelium, and increased vascular endothelin-1 protein content were also noted in HFHS-fed rats compared with control rats. Furthermore, the HFHS diet induced a reduced insulin-stimulated glucose transport activity in muscles and increased levels of NAD(P)H oxidase protein and nitrotyrosine formation in vascular tissues. These findings support the importance of eNOS protein in linking metabolic and vascular disease and indicate the ability of a Westernized diet to induce endothelial dysfunction and to alter metabolic and vascular homeostasis.

  2. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Hyung Joon; Seo, Ha-Rim [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Jeong, Hyo Eun [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Choi, Seung-Cheol; Park, Jae Hyung; Yu, Cheol Woong; Hong, Soon Jun [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Chung, Seok [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Lim, Do-Sun, E-mail: dslmd@kumc.or.kr [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood.

  3. VASCULAR ENDOTHELIAL GROWTH FACTOR IN HEALTH AND DISEASE: A REVIEW

    Directory of Open Access Journals (Sweden)

    Niranjan Gopal

    2016-10-01

    Full Text Available BACKGROUND Vascular Endothelial Growth Factor (VEGF has been implicated as a key molecule, which regulates physiological angiogenesis. VEGF exerts its molecular actions through Receptor Tyrosine Kinases (RTKs VEGFR-1 and VEGFR-2, differ in signaling properties. VEGF plays a vital role in embryogenesis, growth and reproduction. VEGF as a mediator of pathological angiogenesis is associated with proliferation and micrometastasis of various tumours, ocular disorders involving neovascularisation, pre-eclampsia, etc. The pathogenesis of micro and macrovascular complications of diabetes mellitus and the role of VEGF is being studied extensively. Currently, several pharmacological interventions based on VEGF inhibitors and receptor antagonists have been tried to combat the pathological angiogenesis in a wide gamut of disorders. This review attempts to put together important properties, mechanism of action and the role of VEGF in common diseased states. CONCLUSION Effects of VEGF are widespread and have been implicated in several disease states. Therapeutic modalities targeting VEGF have been tried with success in recent years.

  4. Vascular endothelial growth factor blocking agents in retinal vein occlusion

    Directory of Open Access Journals (Sweden)

    Chris Canning

    2008-01-01

    Full Text Available This paper summarises the current status of the use of vascular endothelial growth factor (VEGF blocking agents in retinal vein occlusion. There have been no randomised controlled trials comparing this treatment with the current standard treatment (largely laser so the lower grade evidence of single treatment case series and anecdotal reports are discussed. VEGF blockers are good at reducing macular oedema in the short term, do improve visual acuity in many cases, and do not seem to adversely affect the long term revascularisation that is necessary to overcome the vein occlusion. VEGF blocking agents are not used in isolation in this condition - they will remain an adjunct to systemic and other local treatments. The literature was reviewed in online searches of Embase and Ovid and the papers quoted are a representative sample of a larger body of publications.

  5. Critical Role of Striatin in Blood Pressure and Vascular Responses to Dietary Sodium Intake.

    Science.gov (United States)

    Garza, Amanda E; Pojoga, Luminita H; Moize, Burhanuddin; Hafiz, Wan M; Opsasnick, Lauren A; Siddiqui, Waleed T; Horenstein, Michael; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-09-01

    Striatin is a protein regulator of vesicular trafficking in neurons that also binds caveolin-1 and Ca(2+)-calmodulin and could activate endothelial nitric oxide synthase. We have shown that striatin colocalizes with the mineralocorticoid receptor and that mineralocorticoid receptor activation increases striatin levels in vascular cells. To test whether striatin is a regulator of vascular function, wild-type and heterozygous striatin-deficient mice (Strn(+/-)) were randomized in crossover intervention to restricted (0.03%) and liberal sodium (1.6%) diets for 7 days on each diet, and blood pressure and aortic vascular function were measured. Compared with wild-type, sodium restriction significantly reduced blood pressure in Strn(+/-). On liberal salt intake, phenylephrine and high KCl caused a greater vascular contraction in Strn(+/-) than wild-type, and endothelium removal, nitric oxide synthase inhibitor L-NAME, and guanylate cyclase inhibitor ODQ enhanced phenylephrine contraction to a smaller extent in Strn(+/-) than wild-type. On liberal salt, acetylcholine relaxation was less in Strn(+/-) than in wild-type, and endothelium removal, L-NAME, and ODQ blocked acetylcholine relaxation, suggesting changes in endothelial NO-cGMP. On liberal salt, endothelial nitric oxide synthase mRNA expression and the ratio of endothelial nitric oxide synthase activator pAkt/total Akt were decreased in Strn(+/-) versus wild-type. Vascular relaxation to NO donor sodium nitroprusside was not different among groups. Thus, striatin deficiency is associated with salt sensitivity of blood pressure, enhanced vasoconstriction, and decreased vascular relaxation, suggesting a critical role for striatin, through modulation of endothelial NO-cGMP, in regulation of vascular function and BP during changes in sodium intake.

  6. Levamisole induced apoptosis in cultured vascular endothelial cells

    Science.gov (United States)

    Artwohl, Michaela; Hölzenbein, Thomas; Wagner, Ludwig; Freudenthaler, Angelika; Waldhäusl, Werner; Baumgartner-Parzer, Sabina M

    2000-01-01

    To better understand the anticancer activity of Levamisole (LMS), which serves as an adjuvant in colon cancer therapy in combination with 5-Fluorouracil, this study analyses LMS' ability to induce apoptosis and growth arrest in cultured human micro- and macrovascular endothelial cells (ECs) and fibroblasts. Cells exposed (24 h) to Levamisole (range: 0.5–2 mmol l−1) alone or in combination with antioxidants (10 mmol l−1 glutathione or 5 mmol l−1 N-Acetylcysteine or 0.1 mmol l−1 Tocopherol) were evaluated for apoptosis (3H-thymidine assays, in situ staining), mRNA/protein expression (Northern/Western blot), and proliferation (3H-thymidine incorporation). Levamisole dose-dependently increased apoptosis in ECs to 230% (HUVECs-human umbilical vein ECs), 525% (adult human venous ECs) and 600% (human uterine microvascular ECs) but not in fibroblasts compared to control cells (set as 100%). Levamisole increased in ECs integrin-dependent matrix adhesion, inhibited proliferation (−70%), reduced expression of survival factors such as clusterin (−30%), endothelin-1 (−43%), bcl-2 (−34%), endothelial NO-synthase (−32%) and pRb (Retinoblastoma protein: −89%), and increased that of growth arrest/death signals such as p21 (+73%) and bak (+50%). LMS (2 mmol l−1)-induced apoptosis was inhibited by glutathione (−50%) and N-Acetylcysteine (−36%), which also counteracted reduction by Levamisole of pRb expression, suggesting reactive oxygen species and pRb play a role in these processes. The ability of LMS to selectively induce apoptosis and growth arrest in endothelial cells potentially hints at vascular targeting to contribute to Levamisole's anticancer activity. PMID:11139434

  7. Inhibitive effects of anti-oxidative vitamins on mannitol-induced apoptosis of vascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    PAN Kai-yu; SHEN Mei-ping; YE Zhi-hong; DAI Xiao-na; SHANG Shi-qiang

    2006-01-01

    Objective: Study blood vessel injury and gene expression indicating vascular endothelial cell apoptosis induced by mannitol with and without administration of anti-oxidative vitamins. Methods: Healthy rabbits were randomly divided into four groups. Mannitol was injected into the vein of the rabbit ear in each animal. Pre-treatment prior to mannitol injection was performed with normal saline (group B), vitamin C (group C) and vitamin E (group D). Blood vessel injury was assessed under electron and light microscopy. In a second experiment, cell culture specimen of human umbilical vein endothelial cells were treated with mannitol. Pre-treatment was done with normal saline (sample B), vitamin C (sample C) and vitamin E (sample D).Total RNA was extracted with the original single step procedure, followed by hybridisation and analysis of gene expression.Results: In the animal experiment, serious blood vessel injury was seen in group A and group B. Group D showed light injury only,and normal tissue without pathological changes was seen in group C. Of all 330 apoptosis-related genes analysed in human cell culture specimen, no significant difference was seen after pre-treatment with normal saline, compared with the gene chip without pre-treatment. On the gene chip pre-treated with vitamin C, 45 apoptosis genes were down-regulated and 34 anti-apoptosis genes were up-regulated. Pre-treatment with vitamin E resulted in the down-regulation of 3 apoptosis genes. Conclusion: Vitamin C can protect vascular endothelial cells from mannitol-induced injury.

  8. Endothelial Microparticle-Derived Reactive Oxygen Species: Role in Endothelial Signaling and Vascular Function

    Directory of Open Access Journals (Sweden)

    Dylan Burger

    2016-01-01

    Full Text Available Endothelial microparticles are effectors of endothelial damage; however mechanisms involved are unclear. We examined the effects of eMPs on cultured endothelial cells (ECs and isolated vessels and investigated the role of eMP-derived reactive oxygen species (ROS and redox signaling in these processes. eMPs were isolated from EC media and their ability to directly produce ROS was assessed by lucigenin and liquid chromatography. Nicotinamide adenine dinucleotide phosphate oxidase (Nox subunits were probed by Western blot. ECs were treated with eMPs and effects on kinase signaling, superoxide anion (O2∙- generation, and nitric oxide (NO production were examined. Acetylcholine-mediated vasorelaxation was assessed by myography in eMP-treated mesenteric arteries. eMPs contained Nox1, Nox2, Nox4, p47phox, p67phox, and p22phox and they produced ROS which was inhibited by the Nox inhibitor, apocynin. eMPs increased phosphorylation of ERK1/2 and Src, increased O2∙- production, and decreased A23187-induced NO production in ECs. Pretreatment of eMPs with apocynin diminished eMP-mediated effects on ROS and NO production but had no effect on eMP-mediated kinase activation or impairment in vasorelaxation. Our findings identify a novel mechanism whereby eMP-derived ROS contributes to MP bioactivity. These interactions may be important in conditions associated with vascular injury and increased eMP formation.

  9. Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

    Directory of Open Access Journals (Sweden)

    Raul Velez-Montoya

    2010-08-01

    Full Text Available Raul Velez-Montoya1, Carmen Clapp2, Jose Carlos Rivera2, Gerardo Garcia-Aguirre1, Virgilio Morales-Cantón1, Jans Fromow-Guerra1, Jose Luis Guerrero-Naranjo1, Hugo Quiroz-Mercado31Retina Department Asociación para Evitar la Ceguera en México IAP, México City, México; 2Department of Cellular and Molecular Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México; 3Department of Ophthalmology, Denver Health Medical Center, University of Colorado School of Medicine, Colorado, USAPurpose: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular ­endothelial growth factor in late stages of retinopathy of prematurity.Methods: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05.Results: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001 in the aqueous and vitreous samples.Conclusion: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no ­statistical difference in plasma levels of the molecule between the control and study group

  10. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Institute of Scientific and Technical Information of China (English)

    Yun-Liang Cui; Sheng Zhang; Zhao-Tao Tian; Zhao-Fen Lin; De-Chang Chen

    2016-01-01

    Background:Intact endothelial structure and function are critical for maintaining microcirculatory homeostasis.Dysfunction of the latter is an underlying cause of various organ pathologies.In a previous study,we showed that rhubarb,a traditional Chinese medicine,protected intestinal mucosal microvascular endothelial cells in rats with metastasizing septicemia.In this study,we investigated the effects and mechanisms of rhubarb on matrix metalloproteinase-9 (MMP9)-induced vascular endothelial (VE) permeability.Methods:Rhubarb monomers were extracted and purified by a series of chromatography approaches.The identity of these monomers was analyzed by hydrogen-1 nuclear magnetic resonance (NMR),carbon-13 NMR,and distortionless enhancement by polarization transfer magnetic resonance spectroscopy.We established a human umbilical vein endothelial cell (HUVEC) monolayer on a Transwell insert.We measured the HUVEC permeability,proliferation,and the secretion of VE-cadherin into culture medium using fluorescein isothiocyanate-dextran assay,3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay,and enzyme-linked immunosorbent assay,respectively,in response to treatment with MMP9 and/or rhubarb monomers.Results:A total of 21 rhubarb monomers were extracted and identified.MMP9 significantly increased the permeability of the HUVEC monolayer,which was significantly reduced by five individual rhubarb monomer (emodin,3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid,1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl)-β-D-glucose,daucosterol linoleate,and rhein) or a combination of all five monomers (1 μmol/L for each monomer).Mechanistically,the five-monomer mixture at 1 μmol/L promoted HUVEC proliferation.In addition,MMP9 stimulated the secretion of VE-cadherin into the culture medium,which was significantly inhibited by the five-monomer mixture.Conclusions:The rhubarb mixture of emodin,3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid,1-O-caffeoyl-2-(4-hydroxyl

  11. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Directory of Open Access Journals (Sweden)

    Angela Wang

    2016-12-01

    Full Text Available Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark, orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

  12. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Science.gov (United States)

    Wang, Angela; Leong, Daniel J.; He, Zhiyong; Xu, Lin; Liu, Lidi; Kim, Sun Jin; Hirsh, David M.; Hardin, John A.; Cobelli, Neil J.; Sun, Hui B.

    2016-01-01

    Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling. PMID:27941690

  13. A PROSPECTIVE, OBSERVATIONAL STUDY OF SOLUBLE FLT-1 AND VASCULAR ENDOTHELIAL GROWTH FACTOR IN SEPSIS

    Science.gov (United States)

    Shapiro, Nathan I.; Yano, Kiichiro; Okada, Hitomi; Fischer, Christopher; Howell, Michael; Spokes, Katherine C.; Ngo, Long; Angus, Derek C.; Aird, William C.

    2012-01-01

    Prior murine and human studies suggest that vascular endothelial growth factor (VEGF) contributes to endothelial cell activation and severity of illness in sepsis. Furthermore, circulating levels of soluble VEGF receptor 1 (sFLT) levels were found to increase as part of the early response to sepsis in mice. The objective of the study was to evaluate the blood levels of free VEGF-A and sFLT in patients presenting to the emergency department (ED) with suspected infection and to assess the relationship of these levels with severity of illness and inflammation. It was a prospective, observational study initiated in the ED of an urban, tertiary care, university hospital. Inclusion criteria were (1) ED patients aged 18 years or older and (2) clinical suspicion of infection. Eighty-three patients were enrolled in the study. The major findings were that (1) the mean VEGF and sFLT levels were increasingly higher across the following groups: noninfected control patients, infected patients without shock, and septic shock patients; (2) initial and 24-h VEGF levels had a significant correlation with the presence of septic shock at 24 h; (3) initial and 24-h sFLT levels correlated with Acute Physiology Age Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores initially and at 24 h; and (4) VEGF and sFLT levels correlated with inflammatory cascade activation. This is the first report of sFLT as a potential new marker of severity in patients with sepsis. Vascular endothelial cell growth factor and its signaling axis are important in the endothelial cell response to sepsis, and further elucidation of these mechanisms may lead to advances in future diagnostic and therapeutic opportunities. PMID:18598002

  14. Euterpe oleracea Mart. extract prevents vascular remodeling and endothelial dysfunction in spontaneously hypertensive rats

    Directory of Open Access Journals (Sweden)

    Viviane Silva Cristino Cordeiro

    2015-06-01

    Full Text Available Summary. We assessed the effects of Euterpe oleracea Mart. (açaí seed extract (ASE rich in proanthocyanidins and catechin on vascular dysfunction and oxidative stress associated with hypertension in spontaneously hypertensive rats (SHR. SHR and control rats were treated with ASE (200 mg/kg/day or vehicle for 10 weeks. In the rat mesenteric arterial bed (MAB, acetylcholine response, endothelial nitric oxide synthase (eNOS and superoxide dismutase 1 (SOD 1 expressions were studied. The antioxidant enzyme activity, oxidative damage and nitrite quantification were assessed in MAB and heart homogenates. eNOS immunohistochemistry and histological analysis was carried out on aortic sections. ASE was able to attenuate the hypertension and prevent the endothelial dysfunction in MAB of SHR. The increased levels of protein carbonylation and associated low levels of nitrite in MAB and heart of SHR were attenuated by ASE. The up-regulation of eNOS and SOD1 expression and the increased activity of SOD in MAB from SHR were normalized by ASE. In aorta from SHR, ASE prevented the increase in media thickness, media:lumen ratio and the decrease in the percentage of elastic fibers. Our results suggest that ASE produces antihypertensive effect and prevents the vascular dysfunction in SHR, through mechanisms involving antioxidant effects and NO production. Industrial relevance. Euterpe oleracea Mart. (Açaí has been considered one of the most important medicinal plants of the Amazon by its beneficial effects in the treatment of fever, pain, inflammation and anemia. More recently, Euterpe oleracea Mart. has been reported to reduce blood pressure with an important antioxidant property. The present research reports the protective effect of the extract of the seeds from Euterpe oleraca Mart. against high blood pressure and the associated vascular structural and functional changes. The test for antihypertensive and vascular anti-hypertrophic effect of the hydro

  15. Endothelial Cell Migration and Vascular Endothelial Growth Factor Expression Are the Result of Loss of Breast Tissue Polarity

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Amy; Cuevas, Ileana; Kenny, Paraic A; Miyake, Hiroshi; Mace, Kimberley; Ghajar, Cyrus; Boudreau, Aaron; Bissell, Mina; Boudreau, Nancy

    2009-05-26

    Recruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growth-arrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1{alpha}-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.

  16. Isolation of Endothelial Cells and Vascular Smooth Muscle Cells from Internal Mammary Artery Tissue

    Science.gov (United States)

    Moss, Stephanie C.; Bates, Michael; Parrino, Patrick E.; Woods, T. Cooper

    2007-01-01

    Analyses of vascular smooth muscle cell and endothelial cell function through tissue culture techniques are often employed to investigate the underlying mechanisms regulating cardiovascular disease. As diseases such as diabetes mellitus and chronic kidney disease increase a patient's risk of cardiovascular disease, the development of methods for examining the effects of these diseases on vascular smooth muscle cells and endothelial cells is needed. Commercial sources of endothelial cells and vascular smooth muscle cells generally provide minimal donor information and are in limited supply. This study was designed to determine if vascular smooth muscle cells and endothelial cells could be isolated from human internal mammary arteries obtained from donors undergoing coronary artery bypass graft surgery. As coronary artery bypass graft surgery is a commonly performed procedure, this method would provide a new source for these cells that when combined with the donor's medical history will greatly enhance our studies of the effects of complicating diseases on vascular biology. Internal mammary artery tissue was obtained from patients undergoing coronary artery bypass graft surgery. Through a simple method employing two separate tissue digestions, vascular smooth muscle cells and endothelial cells were isolated and characterized. The isolated vascular smooth muscle cells and endothelial cells exhibited the expected morphology and were able to be passaged for further analysis. The vascular smooth muscle cells exhibited positive staining for α-smooth muscle actin and the endothelial cells exhibited positive staining for CD31. The overall purity of the isolations was > 95%. This method allows for the isolation of endothelial cells and vascular smooth muscle cells from internal mammary arteries, providing a new tool for investigations into the interplay of vascular diseases and complicating diseases such as diabetes and kidney disease. PMID:21603530

  17. Effects of Estrogen Level on the Function of Vascular Endothelial Cells and Expression of Vascular Cell Adhesion Molecule - 1φ

    Institute of Scientific and Technical Information of China (English)

    WU Saizhu(吴赛珠); LIU Jiangguo(刘建国); TAN Jiayu(谭家余); ZHoU Kexiang(周可祥); Gorge D Webb; WEI Heming(隗和明); GUO Zhiguang(郭志刚)

    2002-01-01

    Objectives To ob- serve the effect of different estrogen levels on the se- cretory function of vascular endothelial cells of female rats, and study the effect of modulation of estrogen level on the expression of vascular cell adhesion molecule - 1 and the concentration of estrogen receptorin vascular endothelial cells. Methods Radioim-munology was used to measure the serum concentrationof endothelin and PGI2, and copper-cadmium re-duction was employed to measure the serum content ofnitrogen monoxide. Radioligand binding and flowcy-tometry were used to measure the expression of estrogenreceptor and vascular cell adhesion molecule (VCAM-1 ) of vascular endothelial cells respectively. Re-sults 1. The serum concentration of nitric oxide andPGI2 decreased when the ovaries of female rats wereremoved. In ovariectomized rats, given estrogen, theconcentration rose ( P < 0.05), but the plasma con-centration of endothelin was adverse to it. 2. Theconcentration of estrogen receptor of vascular endothe-lial cells decreased remarkably when the ovaries of fe-male rats were removed. When given estrogen, it in-creased. 3. The percent of expressed VCAM - 1 in-creased siguificantly after interleukin- lβoperated onthe cells, but 17 - βestradiol at 3 × 10-8 ~ 10-6 mol/lall decreased the percent. Conclusions Estrogenlevel can influence the secretion of nitrogen monoxide,PGI2 and endothlin of vascular endothelial cells, andalso influence the concentration of estrogen receptor ofvascular endothelial cells. 17 -β Estradiol at 3 × 10-8~ 10-6 M can decrease the elevation of VCAM - 1 ofvascular endothelial cells induced by interleukin - 1 β.

  18. Response of the sensorimotor cortex of cerebral palsy rats receiving transplantation of vascular endothelial growth factor 165-transfected neural stem cells

    Institute of Scientific and Technical Information of China (English)

    Jielu Tan; Xiangrong Zheng; Shanshan Zhang; Yujia Yang; Xia Wang; Xiaohe Yu; Le Zhong

    2014-01-01

    Neural stem cells are characterized by the ability to differentiate and stably express exogenous ge-nes. Vascular endothelial growth factor plays a role in protecting local blood vessels and neurons of newborn rats with hypoxic-ischemic encephalopathy. Transplantation of vascular endothelial growth factor-transfected neural stem cells may be neuroprotective in rats with cerebral palsy. In this study, 7-day-old Sprague-Dawley rats were divided into ifve groups: (1) sham operation (control), (2) cerebral palsy model alone or with (3) phosphate-buffered saline, (4) vascular en-dothelial growth factor 165 + neural stem cells, or (5) neural stem cells alone. hTe cerebral palsy model was established by ligating the letf common carotid artery followed by exposure to hypox-ia. Phosphate-buffered saline, vascular endothelial growth factor + neural stem cells, and neural stem cells alone were administered into the sensorimotor cortex using the stereotaxic instrument and microsyringe. Atfer transplantation, the radial-arm water maze test and holding test were performed. Immunohistochemistry for vascular endothelial growth factor and histology using hematoxylin-eosin were performed on cerebral cortex. Results revealed that the number of vas-cular endothelial growth factor-positive cells in cerebral palsy rats transplanted with vascular endothelial growth factor-transfected neural stem cells was increased, the time for ifnding water and the ifnding repetitions were reduced, the holding time was prolonged, and the degree of cell degeneration or necrosis was reduced. hTese ifndings indicate that the transplantation of vascu-lar endothelial growth factor-transfected neural stem cells alleviates brain damage and cognitive deifcits, and is neuroprotective in neonatal rats with hypoxia ischemic-mediated cerebral palsy.

  19. Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells.

    Science.gov (United States)

    Ochi, Masanori; Kawai, Yoshiko; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-02-01

    Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 μg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 μg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 μg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3-methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury.

  20. Assessment of vascular and endothelial dysfunction in nutritional studies.

    Science.gov (United States)

    Ray, S; Miglio, C; Eden, T; Del Rio, D

    2014-09-01

    Vascular and endothelial dysfunction (VED) is emerging as a potential set of early markers of cardiovascular disease risk and tests for its measurement have been widely used in clinical research. The aim of this viewpoint is to describe and discuss the current usage of these measures in well-designed nutritional trials, using the potential relationship between fruit juice intake and VED as example. A search was conducted using the NHS evidence portal including studies published in English between January 1980 and October 2013. Only 10 suitable studies were selected, which investigated the effect of fruit juice intake on VED, among which 4 interventions used flow-mediated dilatation, 2 arterial stiffness, 2 a combination of arterial stiffness and flow-mediated dilatation, 2 carotid intimal media thickness and 1 iontophoresis with laser Doppler. Despite minimal effects reported on classical CVD markers, such as lipids, 8 out of the 10 identified studies reported an effect on endothelial function following juice consumption, indicating that VED tests can be effectively used in human dietary interventions to identify relationships between bioactive compounds from fruit and CVD risk. However, paucity of available data, scarcity of compound bioavailability and metabolism information, strong heterogeneity among experimental methodologies and a number of limitations to study designs, still limit the interpretation of the results obtained through these measures. Future, well-designed studies with greater attention to consider use of VED measures are needed to strengthen the utility of VED tests in nutrition research such as those investigating the impact of polyphenol-rich juices and CVD risk.

  1. Osteoblast-conditioned media influence the expression of E-selectin on bone-derived vascular endothelial cells.

    Science.gov (United States)

    Makuch, Lauren A; Sosnoski, Donna M; Gay, Carol V

    2006-08-01

    Breast cancer cells frequently metastasize to the ends of long bones, ribs and vertebrae, structures which contain a rich microvasculature that is closely juxtaposed to metabolically active trabecular bone surfaces. This study focuses on the effects of osteoblast secretions on the surface presentation of adhesive proteins on skeletal vascular endothelial cells. Vascular endothelial cells were isolated from trabecular bone regions of the long bones of 7-week-old Swiss Webster mice and also from the central marrow cavity where trabecular bone is absent. Both types of endothelial cells were placed in culture for 7 days, then exposed 24 h to conditioned media from MC3T3-E1 osteoblasts. Conditioned medium (CM) from two different stages of osteoblast development were tested: (1) from immature MC3T3-E1 cells cultured for 5-7 days and (2) from mature MC3T3-E1 cells cultured for 28-30 days. The immature osteoblasts were in a stage of rapid proliferation; the mature osteoblasts formed a matrix that mineralized. Following exposure to the conditioned media, the vascular cells were exposed to anti-P-selectin, anti-E-selectin, anti-ICAM-1, and anti-VCAM-1 to detect the corresponding adhesive proteins on their surfaces. Breast cancer cells are known to bind to these adhesive proteins. Of the four proteins evaluated, E-selectin was consistently found on more cell surfaces (approximately 30%) of bone-derived vascular endothelial cells (BVECs) when exposed to the immature CM whereas vascular endothelial cells from marrow (MVECs) did not show this response to either immature CM or mature CM. These studies suggest that the BVEC blood vessels near immature bone cells express more surface adhesive protein that could enhance entrapment and extravasation of breast cancer cells. Once cancer cells have undergone extravasation into marrow adjacent to bone, they could be readily attracted to nearby bone surfaces.

  2. Connective tissue: Vascular and hematological (blood) support.

    Science.gov (United States)

    Calvino, Nick

    2003-01-01

    Connective Tissue (CT) is a ubiquitous component of all major tissues and structures of the body (50% of all body protein is CT), including that of the blood, vascular, muscle, tendon, ligament, fascia, bone, joint, IVD's (intervertebral discs) and skin. Because of its ubiquitous nature, CT is an often overlooked component of any essential nutritional program that may address the structure, and/or function of these tissues. The central role of CT in the health of a virtually all cells, tissues, organs, and organ systems, is discussed. General nutritional CT support strategies, as well as specific CT support strategies that focus on blood, vascular, structural system (eg, muscles, tendons, ligaments, fascia, bone, and joints), integument (skin) and inflammatory and immune mediation will be discussed here and will deal with connective tissue dynamics and dysfunction. An overview of the current scientific understanding and possible options for naturally enhancing the structure and function of CT through the application of these concepts will be discussed in this article, with specific attention on the vascular and hematological systems.

  3. Post-transcriptional gene regulation by RNA-binding proteins in vascular endothelial dysfunction.

    Science.gov (United States)

    Xin, HongBo; Deng, KeYu; Fu, MinGui

    2014-08-01

    Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative and migratory capacity of endothelial cells, as well as control of leukocyte trafficking. Endothelial dysfunction is an early step in vascular inflammatory diseases such as atherosclerosis, diabetic vascular complications, sepsis-induced or severe virus infection-induced organ injuries. The expressions of inflammatory cytokines and vascular adhesion molecules induced by various stimuli, such as modified lipids, smoking, advanced glycation end products and bacteria toxin, significantly contribute to the development of endothelial dysfunction. The transcriptional regulation of inflammatory cytokines and vascular adhesion molecules has been well-studied. However, the regulation of those gene expressions at post-transcriptional level is emerging. RNA-binding proteins have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level in microRNA-dependent or independent manners. This review summarizes the latest insights into the roles of RNA-binding proteins in controlling vascular endothelial cell functions and their contribution to the pathogenesis of vascular inflammatory diseases.

  4. Association of Chemerin and Vascular Endothelial Growth Factor (VEGF) with Diabetic Nephropathy

    Science.gov (United States)

    Lin, Shuhua; Teng, Jian; Li, Jixia; Sun, Fang; Yuan, Dong; Chang, Jing

    2016-01-01

    Background Diabetic nephropathy (DN) is a common complication of diabetes, caused by diabetic microvascular lesions. The pathogenesis of DN is complicated, involving genetics, physics, chemistry, and environmental factors. Chemerin is a fat cell factor that participates in regulating inflammation. Vascular endothelial growth factor (VEGF) promotes vascular endothelial cell proliferation, differentiation, and angiogenesis. The relationship role of Chemerin and VEGF in DN is not fully understood. Material/Methods SD rats were randomly divided into 2 groups: the control group and the DN group. Streptozotocin was used to construct the DN model. Serum creatinine (Scr), blood urea nitrogen (BUN), and urine microalbumin (UAlb) were detected. Real-time PCR and Western blot were used to test Chemerin and VEGF mRNA and protein expression in kidney tissue. ELISA was performed to test TGF-β1, TNF-α, and INF-γ levels. The correlation of Chemerin and VEGF with renal function and inflammatory factors was analyzed. Results DN group rats showed obviously increased Scr and BUN levels, and elevated TGF-β1, TNF-α, and INF-γ secretion (P<0.05). Compared with controls, Chemerin and VEGF were clearly overexpressed in the DN group (P<0.05). Chemerin and VEGF expression were positively correlated with inflammatory factors and renal function. Conclusions Chemerin and VEGF play important roles in DN by regulating inflammatory factors and renal function. They may be treated as indicators of DN. PMID:27612613

  5. Effect of Carvedilol on the Coronary Vascular Endothelial Function after Percutaneous Transluminal Coronary Angioplasty

    Institute of Scientific and Technical Information of China (English)

    苏显明; 马奕; 崔长琮

    2003-01-01

    Objectives To understand the effect of carvedilol on the coronary vascular endothelial function of the patients with coronary heart disease after percutaneous transluminal coronary angioplasty (PTCA). Methods 51cases, having one or more than two branches narrow ( ≥ 70% ) , were diagnosed by coronary angiography. These patients were divided randomly into carvedilol group (n = 28 ) and control group (n = 23) who did not take carvedilol.Endothelin (ET) and nitro dioxide (NO) levels of peripheral blood were measured before and after PTCA,before and after two weeks by taking carvedilol. Results Compared with the ET and NO levels before PTCA, ET were markedly increased and NO were decreased after PTCA (p < 0.05); compared with the ET and NO levels before taking carvedilol, ET were decreased and NO were increased after two week (p <0.05) , but the ET and NO levels of the control group did not change in the period of two weeks observation (p > 0.05). Conclusions Carvedilol may improve the coronary vascular endothelial function after PTCA.

  6. Mobilization of endothelial precursor cells: systemic vascular response to musculoskeletal trauma.

    LENUS (Irish Health Repository)

    Laing, A J

    2012-02-03

    Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.

  7. Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.

    Science.gov (United States)

    Nikitopoulou, Ioanna; Orfanos, Stylianos E; Kotanidou, Anastasia; Maltabe, Violetta; Manitsopoulos, Nikolaos; Karras, Panagiotis; Kouklis, Panos; Armaganidis, Apostolos; Maniatis, Nikolaos A

    2016-08-01

    Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH.

  8. Regulation Effect of Vascular Endothelial Growth Factor on Human Fetal Choroid Vascularization

    Institute of Scientific and Technical Information of China (English)

    JinsongZhao; YiWang; 等

    2002-01-01

    Purpose:To investigate the spatial and temporal regulation effect of vascular endothelial growth factor(VEGF) on human fetal choroids vascularization.Methods:The eyeballs of 54 human fetuses from the 9th week to the 40th week due to accidental abortion were studied by immunohistochemically stainin for the expression of VEGF and proliferation cell nuclear antigen (PCNA).Results: (1)The distribution of VEGF expression in the retinal pigment epithelium (RPE) decreased with the incrase of age,the peak of which was between the 9th and 14th week.(2)PCNA immunoreactivity was localized within choriocapillaris endothelium .The expression level decreased alone with fetus age.In this period the choriocapillaris endothelium kept proliferation,differentiation,canalization and remodeled to form the choroids vessels(3)Statistically significant correlations were shown between the expression of VEGF in the PRE and that of PCNA in choriocapillaris endothelium(r=0.933,P<0.01).Couclusin:VEGF expression in PRE was positively involved in modulating human fetal choroids vascularization .Eye Science 2000;16:11-14.

  9. Regulation Effect of Vascular Endothelial Growth Factor on Human Fetal Choroid Vascularization

    Institute of Scientific and Technical Information of China (English)

    Jinsong Zhao; Yue Song; Yi Wang; Xiaoguang Zhang

    2000-01-01

    Purpose: To investigate the spatial and temporal regulation effect of vascular endothelial growth factor(VEGF) on human fetal choroid vascularization. Methods: The eyeballs of 54 human fetuses from the 9th week to the 40th week due to accidental abortion were studied by immunohistochemically staining for the expression of VEGF and proliferation cell nuclear antigen (PCNA). Results: (1) The distribution of VEGF expression in the retinal pigment epithelium (RPE) decreased with the increase of age, the peak of which was between the 9th and 14th week. (2) PCNA immunoreactivity was localized within choriocapillaris endothelium. The expression level decreased alone with fetus age. In this period the choriocapillaris endothelium kept proliferation, differentiation, canalization and remodelled to form the choroid vessels. (3)Statistically significant correlations were shown between the expression of VEGF in the PRE and that of PCNA in choriocapillaris endothelium(r =0. 933, P < 0. 01). Conclusion: VEGF expression in RPE was positively involved in modulating human fetal choroid vascularization. Eye Science 2000; 16:11 ~ 14.

  10. Investigation of the effect of regulating blood antidotal decoction on psoriatic peripheral blood vascular endothelial growth factor level%理血解毒类方对银屑病患者外周血血管内皮生长因子水平的影响

    Institute of Scientific and Technical Information of China (English)

    郝远荣

    2015-01-01

    目的:探讨理血解毒类方对银屑病患者外周血血管内皮生长因子水平的影响。方法:2012年3月-2013年3月收治寻常型银屑病患者100例,根据证候将患者分为血瘀型组、血燥型组和血热型组,其中血瘀型26例,血燥型30例,血热型44例。对照组无银屑病,共35例。使用酶联免疫吸附法检测口服活血解毒汤、养血解毒汤及凉血解毒汤前后患者的血清 VEGF 水平。结果:银屑病患者血清 VEGF 水平在治疗前较对照组明显升高,差异具有统计学意义(P<0.05),血燥型银屑病组治疗前血清VEGF显著低于血热型组,差异具有统计学意义(P<0.05);血热型组与血瘀型组比较差异无统计学意义(P>0.05);血燥型组与血瘀型组比较血清VEGF差异无统计学意义(P>0.05)。中药治疗后血燥型和血热组血清VEGF明显降低(P<0.05),经中药治疗后血瘀型组血清VEGF与治疗前比较差异无统计学意义(P>0.05)。结论:银屑病与VEGF变化具有特异性。养血解毒方、凉血解毒方治疗血燥型和血热型银屑病的机制可能为抑制血管生成。%Objective:To explore the influence of regulating blood antidotal Decoction on psoriatic peripheral blood vascular endothelial growth factor level.Methods:100 patients with psoriasis vulgaris were selected from March 2012 to March 2013.They were divided into the blood dry group with 30 cases, blood heat type with 26 cases and blood stasis type group with 44 cases.35 cases without psoriasis were as the control group.We used enzyme linked immunosorbent assay detected the serum VEGF level of the patients before and after oral Huo Xue Jie Du decoction,detoxification decoction and Liang Xue Jie Du decoction.Results:The serum VEGF level in patients with psoriasis vulgaris before treatment was significantly higher than the control group,with significant difference(P0.05).The level of serum VEGF of blood dryness type group and

  11. Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

    Institute of Scientific and Technical Information of China (English)

    FU Xiao-yan; DING Ming-xing; ZHANG Ning; LIN Xing-qiu; LI Ji-cheng

    2007-01-01

    Objective: To explore the role of vascular endothelial growth factor-C (VEGF-C) in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods: In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density (MVD) were assessed by image analysis. Results: VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors (P<0.05 or P<0.01). In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively (P<0.05 or P<0.01). VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors (P<0.05). VEGFR-3 positive vessels was significantly correlated with MVD(P<0.01). Conclusion: VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.

  12. Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells

    Science.gov (United States)

    Dalal, Samay; Horstmann, Sarah A.; Richens, Tiffany R.; Tanaka, Takeshi; Doe, Jenna M.; Boe, Darren M.; Voelkel, Norbert F.; Taraseviciene-Stewart, Laimute; Janssen, William J.; Lee, Chun G.; Elias, Jack A.; Bratton, Donna; Tuder, Rubin M.; Henson, Peter M.; Vandivier, R. William

    2012-01-01

    Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance. PMID:22307908

  13. Analysis of vascular endothelial dysfunction genes and related pathways in obesity through systematic bioinformatics.

    Science.gov (United States)

    Zhang, Hui; Wang, Jing; Sun, Ling; Xu, Qiuqin; Hou, Miao; Ding, Yueyue; Huang, Jie; Chen, Ye; Cao, Lei; Zhang, Jianmin; Qian, Weiguo; Lv, Haitao

    2015-01-01

    Obesity has become an increasingly serious health problem and popular research topic. It is associated with many diseases, especially cardiovascular disease (CVD)-related endothelial dysfunction. This study analyzed genes related to endothelial dysfunction and obesity and then summarized their most significant signaling pathways. Genes related to vascular endothelial dysfunction and obesity were extracted from a PubMed database, and analyzed by STRING, DAVID, and Gene-Go Meta-Core software. 142 genes associated with obesity were found to play a role in endothelial dysfunction in PubMed. A significant pathway (Angiotensin system maturation in protein folding and maturation) associated with obesity and endothelial dysfunction was explored. The genes and the pathway explored may play an important role in obesity. Further studies about preventing vascular endothelial dysfunction obesity should be conducted through targeting these loci and pathways.

  14. Relationship between vascular endothelial function and pulse wave velocity in prehypertension

    Institute of Scientific and Technical Information of China (English)

    杨娉婷

    2014-01-01

    Objective To investigate the association between vascular endothelial function and arteriosclerosis in prehypertensive,hypertensive and healthy subjects.Methods 810 consecutive subjects were divided into three groups:hypertension group,prehypertension group and control group.Brachial-ankle pulse wave velocity(ba PWV)and flow-mediated brachial artery dilation(FMD)were used to evaluate the artery vascular stiffness and endothelial function respectively.Results Prehypertension

  15. The effects of TSH on human vascular endothelial cells and smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    田利民

    2014-01-01

    Objective To study the effect of thyroid-stimulating hormone(TSH)on human vascular endothelial cells and smooth muscle cells and to explore the roles of TSH in the development of atherosclerosis.Methods Human vascular endothelial cells and smooth muscle cells were cultured in vitro.MTT method was used to assay the effect of TSH on cell viability.Real-time PCR was used

  16. RAPID ENDOTHELIALIZATION OF VASCULAR PROSTHESES BY SEEDING AUTOLOGOUS VENOUS TISSUE FRAGMENTS

    NARCIS (Netherlands)

    NOISHIKI, Y; YAMANE, Y; TOMIZAWA, Y; OKOSHI, T; SATOH, S; WILDEVUUR, CRH; SUZUKI, K

    1992-01-01

    A method was developed to obtain rapid endothelialization of a fabric vascular prosthesis by seeding autologous venous tissue fragments into its wall. In an animal study, complete endothelialization was observed in the entire inner surface of the prosthesis within 2 weeks after implantation. A piece

  17. Preservation of endothelial integrity and function in experimental vascular anastomosis with non-penetrating clips

    NARCIS (Netherlands)

    Zeebregts, C; van den Dungen, J; Buikema, H; Tiebosch, A; van der Want, J; van Schilfgaarde, R

    2001-01-01

    Background: Vascular repair with sutures is associated with disruption of the endothelial lining and subsequent thrombus formation on the intraluminal lesions. This experimental study was designed to determine whether the use of non-penetrating clips improved endothelial preservation. Methods: In te

  18. Impact of Endothelial Microparticles on Coagulation, Inflammation, and Angiogenesis in Age-Related Vascular Diseases

    Directory of Open Access Journals (Sweden)

    Margaret Markiewicz

    2013-01-01

    Full Text Available Endothelial microparticles (EMPs are complex vesicular structures that originate from plasma membranes of activated or apoptotic endothelial cells. EMPs play a significant role in vascular function by altering the processes of inflammation, coagulation, and angiogenesis, and they are key players in the pathogenesis of several vascular diseases. Circulating EMPs are increased in many age-related vascular diseases such as coronary artery disease, peripheral vascular disease, cerebral ischemia, and congestive heart failure. Their elevation in plasma has been considered as both a biomarker and bioactive effector of vascular damage and a target for vascular diseases. This review focuses on the pleiotropic roles of EMPs and the mechanisms that trigger their formation, particularly the involvement of decreased estrogen levels, thrombin, and PAI-1 as major factors that induce EMPs in age-related vascular diseases.

  19. The Study on the Relationship between Serum Vascular Endothelial Growth Factor and Proteinuria in Adriamycin-induced Nephrotic Rats

    Institute of Scientific and Technical Information of China (English)

    ZHU; Zhonghua(

    2001-01-01

    [1]Carmeliet P Collen D.Molecular analysis of blood vessel formation and disease.Am J Physiol 1997 273 :H2091[2]Gleade J M Ebert B L Firth J D.Regulation of angiogenic growth factor expression by hypoxia transition metals and chelating agents.Am J Physiol 1995 268:C1362[3]Uchida K Uchida S.Glomerular endothelial cells in culture express and secrete vascular endothelial growth factor.AmJPhysiol 1994 266:F240[4]Simon M Grone H J Johren O.Expression of vascular endotheial growth factor and its receptors in human renal ontogenetis and adult kidney.Am J Physiol 1995 268:F81[5]Bailey E Bottomley M J.Vascular endothelial growth factor mRNA expression in minimal change membranous and diabetic nephrothy demonstrated by non-isotopic in situ hybridization.J Clin Pathol 1999 52:735[6]Nicholas J A Webb N J Waston C J.Circulation vascular endotheial growth factor is not increased during relapses of steroid-sensitive nephrotic syndrome.Kidney Int 1999 55:1063[7]Shulman K Rosen S Tognazzi K.Expression of VPF is altered in many glomerulous disease.J Am Soc Nephrol 1996 7:661

  20. Eicosanoid signaling and vascular dysfunction: methylmercury-induced phospholipase D activation in vascular endothelial cells.

    Science.gov (United States)

    Sherwani, Shariq I; Pabon, Sheila; Patel, Rishi B; Sayyid, Muzzammil M; Hagele, Thomas; Kotha, Sainath R; Magalang, Ulysses J; Maddipati, Krishna R; Parinandi, Narasimham L

    2013-11-01

    Mercury, especially methylmercury (MeHg), is implicated in the etiology of cardiovascular diseases. Earlier, we have reported that MeHg induces phospholipase D (PLD) activation through oxidative stress and thiol-redox alteration. Hence, we investigated the mechanism of the MeHg-induced PLD activation through the upstream regulation by phospholipase A2 (PLA2) and lipid oxygenases such as cyclooxygenase (COX) and lipoxygenase (LOX) in the bovine pulmonary artery endothelial cells (BPAECs). Our results showed that MeHg significantly activated both PLA2 (release of [(3)H]arachidonic acid, AA) and PLD (formation of [(32)P]phosphatidylbutanol) in BPAECs in dose- (0-10 μM) and time-dependent (0-60 min) fashion. The cPLA2-specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), significantly attenuated the MeHg-induced [(3)H]AA release in ECs. MeHg-induced PLD activation was also inhibited by AACOCF3 and the COX- and LOX-specific inhibitors. MeHg also induced the formation of COX- and LOX-catalyzed eicosanoids in ECs. MeHg-induced cytotoxicity (based on lactate dehydrogenase release) was protected by PLA2-, COX-, and LOX-specific inhibitors and 1-butanol, the PLD-generated PA quencher. For the first time, our studies showed that MeHg activated PLD in vascular ECs through the upstream action of cPLA2 and the COX- and LOX-generated eicosanoids. These results offered insights into the mechanism(s) of the MeHg-mediated vascular endothelial cell lipid signaling as an underlying cause of mercury-induced cardiovascular diseases.

  1. Vascular endothelial growth factor-B promotes in vivo angiogenesis.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Tamarat, Radia; Ebrahimian, Teni G; Le-Roux, Aude; Clergue, Michel; Emmanuel, Florence; Duriez, Micheline; Schwartz, Bertrand; Branellec, Didier; Lévy, Bernard I

    2003-07-25

    Vascular endothelial growth factors (VEGFs) and their receptors have emerged as central regulators of the angiogenic process. However, involvement of VEGF-B, one of these factors, in angiogenesis remains obscure. Mice received subcutaneous injection of Matrigel alone or Matrigel with human recombinant protein rhVEGF-B167 or with rhVEGF-A165. After 14 days, cell ingrowth in the Matrigel plug was increased by 2.0- and 2.5-fold in rhVEGF-B167-treated and rhVEGF-A165-treated mice, respectively (P<0.01), in association with a raise in phospho-Akt/Akt (1.8-fold, P<0.01) and endothelial NO synthase (eNOS) (1.80- and 1.60-fold, respectively; P<0.05) protein levels measured by Western blot. VEGF-B-induced cell ingrowth was impaired by treatment with NOS inhibitor (NG-nitro-l-arginine methyl ester; L-NAME, 10 mg/kg per day). Treatment with neutralizing antibody directed against the VEGF-B receptor VEGF-R1 (anti-VEGFR1, 10 microg) completely abrogated VEGF-B-related effects. Proangiogenic effect of VEGF-B was confirmed in a mouse model of surgically induced hindlimb ischemia. Plasmids containing human form of VEGF-A (phVEGF-A165) or VEGF-B (phVEGF-B167 or phVEGF-B186) were administered by in vivo electrotransfer. Angiographic score at day 28 showed significant improvement in ischemic/nonischemic leg ratio by 1.4- and 1.5-fold in mice treated with phVEGF-B167 and phVEGF-B186, respectively (P<0.05). Laser Doppler perfusion data also evidenced a 1.5-fold increase in phVEGF-B167-treated and phVEGF-B186-treated mice (P<0.05). Such an effect was associated with an upregulation of phospho-Akt/Akt and eNOS protein levels in the ischemic legs and was hampered by treatment with anti-VEGFR1. This study demonstrates for the first time that VEGF-B, in part through its receptor VEGF-R1, promotes angiogenesis in association with an activation of Akt and eNOS-related pathways.

  2. Effects of vascular endothelial growth factor on survival of surgical flaps: a review of experimental studies.

    Science.gov (United States)

    Fang, Taolin; Lineaweaver, William C; Chen, Michael B; Kisner, Carson; Zhang, Feng

    2014-01-01

    Partial or complete necrosis of skin flaps remains a significant problem in plastic and reconstructive surgery. Growth factors have shown promise in improving flap survival through increased angiogenesis and blood supply to the flap. Vascular endothelial growth factor (VEGF) is the most widely investigated and successful one. But the mechanisms of the effects are still not very clear. In the course of a series of experiments, we indicated that tissue survival of surgical flaps could be improved by both preoperative (sustained phase effect) and intraoperative (acute phase effect) application of VEGF. We reviewed both experimental and clinical investigations on the use of VEGF with surgical flaps to summarize the evidence of both phases of VEGF activity in promotion of flaps survival in detail. With the combinations of acute and sustained phases of effects, VEGF protein and gene, VEGF morphologic actions, and VEGF histochemical modulations suggest a pattern of VEGF activity that can be superimposed on classic descriptive mechanisms of tissue survival of flaps.

  3. Vascular endothelial growth factor and not cyclooxygenase 2 promotes endothelial cell viability in the pancreatic tumor microenvironment.

    LENUS (Irish Health Repository)

    Toomey, Desmond P

    2010-07-01

    Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation.

  4. Stem cell-derived vascular endothelial cells and their potential application in regenerative medicine

    Science.gov (United States)

    Although a 'vascular stem cell' population has not been identified or generated, vascular endothelial and mural cells (smooth muscle cells and pericytes) can be derived from currently known pluripotent stem cell sources, including human embryonic stem cells and induced pluripotent stem cells. We rev...

  5. Study on the biological characteristics of pancreatic cancer vascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    李雷

    2012-01-01

    Objective To explore the biological characteristics of pancreatic cancer vascular endothelial cells,including the aspects of morphology,species,genetics,vascular formation ability,and proliferation ability in vitro. Methods The human pancreatic cancer cells were inoculated in nude mice pancreas to get pancreatic cancer

  6. VASCULAR ENDOTHELIAL GROWTH FACTORS IN HEART TRANSPLANT REJECTIONS

    Directory of Open Access Journals (Sweden)

    O. P. Shevchenko

    2015-01-01

    Full Text Available Aim: to determine the clinical significance of vascular endothelial growth factors VEGF-A, VEGF-D, PlGF-1 to assess the risk of cardiovascular complications in heart recipients. Materials and methods. 103 patients, aged 16 to 73 years, 85 males and 18 females. 65 recipients (47 men and 18 women had dilated cardiomyopathy, 38 – coronary heart disease (CHD. The concentration of VEGF-A, VEGF-D, PlGF-1 was measured using xMAP technology with sets of reagents Simplex ProcartaPlex™. Results. After HTx the level of VEGF-A significantly decreased, p = 0.001. There were no correlations between the levels of VEGF-A, VEGF-D and PlGF-1 with age, gender and diagnosis. After HTx VEGF-A level was higher in recipients with ACR than in those without it (p = 0.001. ACR frequency was significantly higher in patients with high VEGF-A level (≥316.5 pg/ml, RR = 5.8 ± 0.5, AUC = 0.779. After HTx PlGF-1 level was higher in recipients with ACR too (p = 0.039. ACR frequency was significantly higher in patients with high PlGF-1 level (≥5.33 pg/ml, RR = 1.8 ± 0.5, AUC = 0.65. There were no correlations between VEGF-D level with ACR and all three biomarkers with AMR. ACR frequency was significantly higher with both high VEGF-A and PlGF-1 levels (RR = 6.4. Conclusion. Serum levels of VEGF-A and PlGF-1 after HTx may be regarded as indicators of increased risk of ACR.

  7. A novel mechanism of diabetic vascular endothelial dysfunction: Hypoadiponectinemia-induced NLRP3 inflammasome activation.

    Science.gov (United States)

    Zhang, Jinglong; Xia, Linying; Zhang, Fen; Zhu, Di; Xin, Chao; Wang, Helin; Zhang, Fuyang; Guo, Xian; Lee, Yan; Zhang, Ling; Wang, Shan; Guo, Xiong; Huang, Chong; Gao, Feng; Liu, Yi; Tao, Ling

    2017-02-12

    It has been well documented that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. However, the exact molecular mechanism which mediates this process has not been fully described. The current study aimed to investigate the role of hypoadiponectinemia-induced NLRP3 inflammasome activation in diabetic vascular endothelial dysfunction and its molecular mechanism. Male adult adiponectin knockout mice and wild type mice were fed with a high fat diet to establish a type 2 diabetic mellitus model. In addition, human umbilical vein endothelial cells (HUVECs) were cultured and subjected to high glucose/high fat (HG/HF). The NLRP3 inflammasome activation was increased in type 2 diabetic mice and treatment of diabetic aortic segments with MCC950, a potent selective inhibitor of NLRP3 inflammasome ex vivo improved endothelial-dependent vasorelaxation. NLRP3 inflammasome activation and vascular endothelial injury were significantly increased in APN-KO mice compared with WT mice in diabetes and MCC950 decreased diabetic vascular endothelial dysfunction to comparable levels in APN-KO mice and WT mice. Adiponectin could decrease NLRP3 inflammasome activation and attenuate endothelial cell injury, which was abolished by NLRP3 inflammasome overexpression. Inhibition of peroxynitrite formation preferentially attenuated NLRP3 inflammasome activation in APN-KO diabetic mice. The current study demonstrated for the first time that hypoadiponectinemia-induced NLRP3 inflammasome activation was a novel mechanism of diabetic vascular endothelial dysfunction.

  8. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.

    Science.gov (United States)

    Dulak, Jozef; Józkowicz, Alicja; Foresti, Roberta; Kasza, Aneta; Frick, Matthias; Huk, Ihor; Green, Colin J; Pachinger, Otmar; Weidinger, Franz; Motterlini, Roberto

    2002-04-01

    Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.

  9. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.M.; Doornbos, R.P.; Witkamp, R.F.; Greef, de J.; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (ß2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents

  10. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.; Doornbos, R.P.; Witkamp, R.F.; Greef, J. van der; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (beta2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agen

  11. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.M.; Doornbos, R.P.; Witkamp, R.F.; Greef, J. van der; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (β2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents

  12. Roles of vascular endothelial growth factor, blood hydrocortisone and urinary catecholamines in obstructive sleep apnea-hypopnea syndrome%血管内皮生长因子、血清皮质醇、尿儿茶酚胺在阻塞性睡眠呼吸暂停低通气综合征中的意义探讨

    Institute of Scientific and Technical Information of China (English)

    林其昌; 黄建钗; 丁海波; 王春娥; 曾春艳; 李树奇

    2009-01-01

    目的 检测阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)患者血管内皮生长因子(vascular endothelial growth factor,VEGF)、血清皮质醇及夜间尿儿茶酚胺(UCA)的浓度,初步探讨其在OSAHS并发心脑血管疾病中的意义.方法 65例OSAHS合并心脑血管病患者、70例单纯OSAHS患者、74例正常对照组,检测血浆VEGF、血清皮质醇和夜间UCA浓度.结果 血浆VEGF、血清皮质醇及夜间UCA在OSAHS患者高于正常人,OSAHS合并心脑血管病患者更高,差异均有统计学意义(P<0.05).结论 OSAHS患者血浆VEGF、血清皮质醇和夜间UCA浓度均较正常对照组升高;合并心脑血管病的OSAHS患者比单纯OSAHS患者血浆VEGF、血清皮质醇和夜间UCA浓度升高更显著;血浆VEGF、血清皮质醇及夜间UCA浓度升高在OSAHS患者并发心脑血管疾病中可能起着重要作用.%Objective To test the concentrations of vascular endothelial growth factor(VEGF),blood hydrocortisonc and night urinary catecholamines(UCA) in patients with obstructive sleep apnea-hypopnea syndrome(OSAHS) and probe into their roles in OSAHS with cardiovascular or ccrebrovascular disease. Methods The concentrations of VEGF, blood hydrocortisone and night UCA were tested in 65 OSAHS patients with cardiovascular or cerebrovascular diseases, 70 OSAHS patients without cardiovascular or cerebrovascular diseases and 74 healthy adults. Results The concentrations of VEGF,blood hydrocortisone and night UCA in OSAHS patients were found to be significantly higher compared with those of healthy subjects,the concentrations in OSAHS patients with cardiovascular or cerebrovascular diseases were more higher( P<0.05). Conclusions The concentrations of VEGF, blood hydrocortisone and night UCA rise in patients with OSAHS and those of OSAHS patients with cardiovascular or cerebrovaseular diseases rise more evidently. VEGF, blood hydrocortisone and night UCA may contribute to the

  13. The use of adipose mesenchymal stem cells and human umbilical vascular endothelial cells on a fibrin matrix for endothelialized skin substitute.

    Science.gov (United States)

    Sánchez-Muñoz, Isabel; Granados, Rosario; Holguín Holgado, Purificación; García-Vela, José Antonio; Casares, Celia; Casares, Miguel

    2015-01-01

    In recent years, the reconstruction of human skin by tissue engineering represents a clinical challenge and has offered a therapeutic alternative. Avascular engineered skin equivalents have been available for several years and used to treat wounds due to burns, nonhealing ulcers, and surgical excisions. They are constituted by different types of cultured cells included in a three-dimensional structure that permits cellular proliferation to create tissue substitutes. The major drawback of these artificial skin substitutes is their lack of blood supply, since the endurance and cell proliferation of the substitute depend on an adequate oxygen and nutrient supply and on toxin removal. These functions are served by the vascular system. We have produced a new model of endothelialized skin substitute that promotes the formation of capillary-like structures by seeding human umbilical vein endothelial cells (HUVECs) with dermal fibroblasts and human adipose-derived mesenchymal stem cells (hADMSCs) in a fibrin matrix. Dermal fibroblasts and hADMSCs produce extracellular matrix that stimulates cellular growth and proliferation. hADMSCs secrete significant quantities of angiogenic and antiapoptotic factors (vascular endothelial growth factor and hepatocyte growth factor), which induce in vitro differentiation of these cells into endothelial cells promoting angiogenesis and participating in tissue repair and skin regeneration processes. We obtained the artificial skin substitute with similar structure to native skin, including dermis and epidermis. We demonstrated that endothelial cells (CD31 and von Willebrand factor positive) proliferated and organized themselves into capillary-like structures within the fibrin matrix. The epidermis showed a complete epithelization by squamous cells (AE1/AE3 cytokeratin positive) with intracytoplasmic keratohyalin granules, hyperkeratosis, and parakeratosis. We have established a novel artificial skin substitute that facilitates the formation

  14. Effect of immobilized collagen type IV on biological properties of endothelial cells for the enhanced endothelialization of synthetic vascular graft materials.

    Science.gov (United States)

    Heo, Yunhoe; Shin, Young Min; Lee, Yu Bin; Lim, Youn Mook; Shin, Heungsoo

    2015-10-01

    Regeneration of healthy endothelium onto vascular graft materials is imperative for prevention of intimal hyperplasia and thrombogenesis. In this study, we investigated the effect of collagen type IV (COL-IV) immobilized onto electrospun nanofibers on modulation of endothelial cell (EC) function, as a potential signal to rapid endothelialization of vascular grafts. COL-IV is assembled in basement membrane underneath intimal layer and regulates morphogenesis of blood vessels. For immobilization of COL-IV, poly(l-lactic acid) (PLLA) nanofibers (PL) were prepared as a model vascular graft substrate, onto which acrylic acid (AAc) was then grafted by using gamma-ray irradiation. AAc graft was dependent on irradiation doses and AAc concentrations, which allowed us to select the condition of 5% (v/v) AAc and 10 kGy for further conjugation of COL-IV. COL-IV immobilization was proportionally controlled as a function of its concentration. Atomic force microscope (AFM) analysis qualitatively supported immobilization of COL-IV, demonstrating increase in root mean square roughness of the PL from 665.37 ± 13.20 nm to 1440.74 ± 33.24. However, the Young's modulus of nanofibers was retained as approximately 1 MPa, regardless of surface modification. The number of ECs attached on the nanofibers with immobilized COL-IV was significantly increased by 5 times (1052 ± 138 cells/mm(2)) from pristine PL (234 ± 41 cells/mm(2)). In addition, the effect of immobilized COL-IV was profound for enhancing proliferation and up-regulation of markers implicated in rapid endothelialization. Collectively, our results suggest that COL-IV immobilized onto electrospun PLLA nanofibers may serve as a promising instructive cue used in vascular graft materials.

  15. The small fibrinopeptide Bβ15-42 as renoprotective agent preserving the endothelial and vascular integrity in early ischemia reperfusion injury in the mouse kidney.

    Directory of Open Access Journals (Sweden)

    Anja Urbschat

    Full Text Available Disruption of the renal endothelial integrity is pivotal for the development of a vascular leak, tissue edema and consequently acute kidney injury. Kidney ischemia amplifies endothelial activation and up-regulation of pro-inflammatory mechanisms. After restoring a sufficient blood flow, the kidney is damaged through complex pathomechanisms that are classically referred to as ischemia and reperfusion injury, where the disruption of the inter-endothelial connections seems to be a crucial step in this pathomechanism. Focusing on the molecular cell-cell interaction, the fibrinopeptide Bβ15-42 prevents vascular leakage by stabilizing these inter-endothelial junctions. The peptide associates with vascular endothelial-cadherin, thus preventing early kidney dysfunction by preserving blood perfusion efficacy, edema formation and thus organ dysfunction. We intended to demonstrate the early therapeutic benefit of intravenously administered Bβ15-42 in a mouse model of renal ischemia and reperfusion. After 30 minutes of ischemia, the fibrinopeptide Bβ15-42 was administered intravenously before reperfusion was commenced for 1 and 3 hours. We show that Bβ15-42 alleviates early functional and morphological kidney damage as soon as 1 h and 3 h after ischemia and reperfusion. Mice treated with Bβ15-42 displayed a significantly reduced loss of VE-cadherin, indicating a conserved endothelial barrier leading to less neutrophil infiltration which in turn resulted in significantly reduced structural renal damage. The significant reduction in tissue and serum neutrophil gelatinase-associated lipocalin levels reinforced our findings. Moreover, renal perfusion analysis by color duplex sonography revealed that Bβ15-42 treatment preserved resistive indices and even improved blood velocity. Our data demonstrate the efficacy of early therapeutic intervention using the fibrinopeptide Bβ15-42 in the treatment of acute kidney injury resulting from ischemia and

  16. Hydrogen-Rich Medium Attenuated Lipopolysaccharide-Induced Monocyte-Endothelial Cell Adhesion and Vascular Endothelial Permeability via Rho-Associated Coiled-Coil Protein Kinase.

    Science.gov (United States)

    Xie, Keliang; Wang, Weina; Chen, Hongguang; Han, Huanzhi; Liu, Daquan; Wang, Guolin; Yu, Yonghao

    2015-07-01

    Sepsis is the leading cause of death in critically ill patients. In recent years, molecular hydrogen, as an effective free radical scavenger, has been shown a selective antioxidant and anti-inflammatory effect, and it is beneficial in the treatment of sepsis. Rho-associated coiled-coil protein kinase (ROCK) participates in junction between normal cells, and regulates vascular endothelial permeability. In this study, we used lipopolysaccharide to stimulate vascular endothelial cells and explored the effects of hydrogen-rich medium on the regulation of adhesion of monocytes to endothelial cells and vascular endothelial permeability. We found that hydrogen-rich medium could inhibit adhesion of monocytes to endothelial cells and decrease levels of adhesion molecules, whereas the levels of transepithelial/endothelial electrical resistance values and the expression of vascular endothelial cadherin were increased after hydrogen-rich medium treatment. Moreover, hydrogen-rich medium could lessen the expression of ROCK, as a similar effect of its inhibitor Y-27632. In addition, hydrogen-rich medium could also inhibit adhesion of polymorphonuclear neutrophils to endothelial cells. In conclusion, hydrogen-rich medium could regulate adhesion of monocytes/polymorphonuclear neutrophils to endothelial cells and vascular endothelial permeability, and this effect might be related to the decreased expression of ROCK protein.

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

    NARCIS (Netherlands)

    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 progeni

  18. Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor

    NARCIS (Netherlands)

    Ferreras, C.; Rushton, G.; Cole, C.L.; Babur, Muhammad; Telfer, B.A.; Kuppevelt, A.H. van; Gardiner, J.M.; Williams, K.J.; Jayson, G.C.; Avizienyte, E.

    2012-01-01

    Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FG

  19. Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

    Science.gov (United States)

    Liu, Chun-Hsiu; Su, Wei-Wen; Shie, Shian-Sen; Cheng, Shih-Tsung; Su, Cheng-Wen; Ho, Wang-Jing

    2016-03-01

    The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ± 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ± 0.67 dB/y, inferior field -0.10 ± 0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression.

  20. Family with sequence similarity 5, member C (FAM5C increases leukocyte adhesion molecules in vascular endothelial cells: implication in vascular inflammation.

    Directory of Open Access Journals (Sweden)

    Junya Sato

    Full Text Available Identification of the regulators of vascular inflammation is important if we are to understand the molecular mechanisms leading to atherosclerosis and consequent ischemic heart disease, including acute myocardial infarction. Gene polymorphisms in family with sequence similarity 5, member C (FAM5C are associated with an increased risk of acute myocardial infarction, but little is known about the function of this gene product in blood vessels. Here, we report that the regulation of the expression and function of FAM5C in endothelial cells. We show here that FAM5C is expressed in endothelial cells in vitro and in vivo. Immunofluorescence microscopy showed localization of FAM5C in the Golgi in cultured human endothelial cells. Immunohistochemistry on serial sections of human coronary artery showed that FAM5C-positive endothelium expressed intercellular adhesion molecule-1 (ICAM-1 or vascular cell adhesion molecule-1 (VCAM-1. In cultured human endothelial cells, the overexpression of FAM5C increased the reactive oxygen species (ROS production, nuclear factor-κB (NF-κB activity and the expression of ICAM-1, VCAM-1 and E-selectin mRNAs, resulting in enhanced monocyte adhesion. FAM5C was upregulated in response to inflammatory stimuli, such as TNF-α, in an NF-κB- and JNK-dependent manner. Knockdown of FAM5C by small interfering RNA inhibited the increase in the TNF-α-induced production of ROS, NF-κB activity and expression of these leukocyte adhesion molecule mRNAs, resulting in reduced monocyte adhesion. These results suggest that in endothelial cells, when FAM5C is upregulated in response to inflammatory stimuli, it increases the expression of leukocyte adhesion molecules by increasing ROS production and NF-κB activity.

  1. Recent advances in understanding the roles of vascular endothelial cells in allergic inflammation.

    Science.gov (United States)

    Shoda, Tetsuo; Futamura, Kyoko; Orihara, Kanami; Emi-Sugie, Maiko; Saito, Hirohisa; Matsumoto, Kenji; Matsuda, Akio

    2016-01-01

    Allergic disorders commonly involve both chronic tissue inflammation and remodeling caused by immunological reactions to various antigens on tissue surfaces. Due to their anatomical location, vascular endothelial cells are the final responders to interact with various exogenous factors that come into contact with the epithelial surface, such as pathogen-associated molecular patterns (PAMPs) and antigens. Recent studies have shed light on the important roles of endothelial cells in the development and exacerbation of allergic disorders. For instance, endothelial cells have the greatest potential to produce several key molecules that are deeply involved in allergic inflammation, such as periostin and thymus and activation-regulated chemokine (TARC/CCL17). Additionally, endothelial cells were recently shown to be important functional targets for IL-33--an essential regulator of allergic inflammation. Notably, almost all endothelial cell responses and functions involved in allergic inflammation are not suppressed by corticosteroids. These corticosteroid-refractory endothelial cell responses and functions include TNF-α-associated angiogenesis, leukocyte adhesion, IL-33-mediated responses and periostin and TARC production. Therefore, these unique responses and functions of endothelial cells may be critically involved in the pathogenesis of various allergic disorders, especially their refractory processes. Here, we review recent studies, including ours, which have elucidated previously unknown pathophysiological roles of vascular endothelial cells in allergic inflammation and discuss the possibility of endothelium-targeted therapy for allergic disorders.

  2. Recent advances in understanding the roles of vascular endothelial cells in allergic inflammation

    Directory of Open Access Journals (Sweden)

    Tetsuo Shoda

    2016-01-01

    Full Text Available Allergic disorders commonly involve both chronic tissue inflammation and remodeling caused by immunological reactions to various antigens on tissue surfaces. Due to their anatomical location, vascular endothelial cells are the final responders to interact with various exogenous factors that come into contact with the epithelial surface, such as pathogen-associated molecular patterns (PAMPs and antigens. Recent studies have shed light on the important roles of endothelial cells in the development and exacerbation of allergic disorders. For instance, endothelial cells have the greatest potential to produce several key molecules that are deeply involved in allergic inflammation, such as periostin and thymus and activation-regulated chemokine (TARC/CCL17. Additionally, endothelial cells were recently shown to be important functional targets for IL-33—an essential regulator of allergic inflammation. Notably, almost all endothelial cell responses and functions involved in allergic inflammation are not suppressed by corticosteroids. These corticosteroid-refractory endothelial cell responses and functions include TNF-α-associated angiogenesis, leukocyte adhesion, IL-33-mediated responses and periostin and TARC production. Therefore, these unique responses and functions of endothelial cells may be critically involved in the pathogenesis of various allergic disorders, especially their refractory processes. Here, we review recent studies, including ours, which have elucidated previously unknown pathophysiological roles of vascular endothelial cells in allergic inflammation and discuss the possibility of endothelium-targeted therapy for allergic disorders.

  3. Expression and Purification of Functional Human Vascular Endothelial Growth Factor-A121; the Most Important Angiogenesis Factor

    Directory of Open Access Journals (Sweden)

    Fatemeh Kazemi-Lomedasht

    2014-12-01

    Full Text Available Purpose: Angiogenesis or formation of new blood vessels is an essential process for tumor growth, invasion and metastasis. Vascular Endothelial Growth Factor (VEGF and its receptors play an important role in angiogenesis-dependent tumors. VEGF-A is the most important factor in angiogenesis process. Human VEGF-A gene consists of eight exons that undergoes alternative exon splicing and produce five different proteins consisting of 121, 145, 165, 189 and 206 amino acids (named VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206. Methods: In this study, VEGF121 gene synthesized and cloned into the pET-26b plasmid. The recombinant plasmid was transferred into appropriate expression strain of BL-21. Expression of VEGF121 induced by IPTG (Isopropyl β-D-1-thiogalactopyranoside and confirmed by SDS-PAGE and Western-Blotting. Recombinant VEGF121 was purified by nickel affinity chromatography. HUVECs (Human Umbilical Vein Endothelia Cells cells were isolated from umbilical vein and the effect of VEGF121 on tube formation of endothelial cells was investigated. Results: SDS-PAGE and Western-Blotting results verified the purification of VEGF121. The final yield of recombinant protein was about 5mg per liter. Endothelial cell tube formation assay results showed that VEGF121 leads to tube formation of endothelial cell on matrix and induces angiogenesis in vitro. Conclusion: Recombinant VEGF121 is important factor in tube formation of endothelial cell, so it could be used in different cancer researches and angiogenesis assay.

  4. Vascular Endothelial Growth Factor-Related Pathways in Hemato-Lymphoid Malignancies

    Directory of Open Access Journals (Sweden)

    Michael Medinger

    2010-01-01

    Full Text Available Angiogenesis is essential for malignant tumor growth. This has been documented for solid tumors, and there is an emerging evidence suggesting that tumor progression of hematolymphoid malignancies also depends on the induction of new blood vessel formation. The most important proangiogenic agent is vascular endothelial growth factor (VEGF, activating VEGF receptors 1 and 2. The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. Several antiangiogenic agents targeting VEGF-related pathways are also being utilized in clinical trials for the treatment of hemato-lymphoid malignancies, and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hemato-lymphoid malignancies and the translation of such basic findings into clinical studies.

  5. Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.

    Science.gov (United States)

    Ochi, Masanori; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-01-01

    Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

  6. New Indices of Endothelial Function Measured by Digital Thermal Monitoring of Vascular Reactivity: Data from 6084 Patients Registry

    Directory of Open Access Journals (Sweden)

    Morteza Naghavi

    2016-01-01

    Full Text Available Background. Endothelial function is viewed as a barometer of cardiovascular health and plays a central role in vascular reactivity. Several studies showed digital thermal monitoring (DTM as a simple noninvasive method to measure vascular reactivity that is correlated with atherosclerosis risk factors and coronary artery disease. Objectives. To further evaluate the relations between patient characteristics and DTM indices in a large patient registry. Methods. DTM measures were correlated with age, sex, heart rate, and systolic and diastolic blood pressure in 6084 patients from 18 clinics. Results. DTM vascular reactivity index (VRI was normally distributed and inversely correlated with age (r=-0.21, p<0.0001. Thirteen percent of VRI tests were categorized as poor vascular reactivity (VRI < 1.0, 70 percent as intermediate (1.0 ≤ VRI < 2.0, and 17 percent as good (VRI ≥ 2.0. Poor VRI (<1.0 was noted in 6% of <50 y, 10% of 50–70 y, and 18% of ≥70 y. In multiple linear regression analyses, age, sex, and diastolic blood pressure were significant but weak predictors of VRI. Conclusions. As the largest database of finger-based vascular reactivity measurement, this report adds to prior findings that VRI is a meaningful physiological marker and reflects a high level of residual risk found in patients currently under care.

  7. Different contributions of clathrin- and caveolae-mediated endocytosis of vascular endothelial cadherin to lipopolysaccharide-induced vascular hyperpermeability.

    Science.gov (United States)

    Zhang, Ye; Zhang, Lianyang; Li, Yang; Sun, Shijin; Tan, Hao

    2014-01-01

    Vascular hyperpermeability induced by lipopolysaccharide (LPS) is a common pathogenic process in cases of severe trauma and sepsis. Vascular endothelial cadherin (VE-cad) is a key regulatory molecule involved in this process, although the detailed mechanism through which this molecule acts remains unclear. We assessed the role of clathrin-mediated and caveolae-mediated endocytosis of VE-cad in LPS-induced vascular hyperpermeability in the human vascular endothelial cell line CRL-2922 and determined that vascular permeability and VE-cad localization at the plasma membrane were negatively correlated after LPS treatment. Additionally, the loss of VE-cad at the plasma membrane was caused by both clathrin-mediated and caveolae-mediated endocytosis. Clathrin-mediated endocytosis was dominant early after LPS treatment, and caveolae-mediated endocytosis was dominant hours after LPS treatment. The caveolae-mediated endocytosis of VE-cad was activated through the LPS-Toll-like receptor 4 (TLR4)-Src signaling pathway. Structural changes in the actin cytoskeleton, specifically from polymerization to depolymerization, were important reasons for the switching of the VE-cad endocytosis pathway from clathrin-mediated to caveolae-mediated. Our findings suggest that clathrin-mediated and caveolae-mediated endocytosis of VE-cad contribute to LPS-induced vascular hyperpermeability, although they contribute via different mechanism. The predominant means of endocytosis depends on the time since LPS treatment.

  8. Beta-lactam antibiotic-mediated changes in platelet reactivity and vascular endothelial functions.

    Science.gov (United States)

    Togna, G I; Togna, A R; Caprino, L

    2001-05-01

    To evaluate vascular and platelet compatibility of intravenous administration of beta-lactam antibiotics, we assessed the effects of therapeutic concentrations of ceftriaxone, aztreonam, and ceftazidime on platelet reactivity to different agonists (sodium arachidonate, collagen and adenosine diphosphate) and on selected vascular endothelial functions (adenosine diphosphatase activity, prostacyclin production and t-PA release). Ceftriaxone and, to a lesser degree, aztreonam, enhanced platelet reactivity, evaluated as onset of platelet aggregating response, and increased thromboxane production to subthreshold concentrations of arachidonate. There was no modification in platelet reactivity after ceftazidime treatment. Ceftriaxone and ceftazidime, but not aztreonam, inhibited endothelial adenosine diphosphatase activity. Prostacyclin production and t-PA release were inhibited only by ceftriaxone at high concentrations. While it is difficult to establish which marker (platelet or endothelial functions) has more clinical reference in human vascular compatibility, it seems feasible to consider aztreonam the most compatible of the beta-lactams studied.

  9. Effect of Solitaire AB stent thrombectomy on vascular endothelial function and inflammatory cytokines in patients with progressive cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Zhi-Bao Wu; Xue-Juan Han; Zi-Hao Zhang; Wen-Liang Zhang; Liang Liu

    2016-01-01

    Objective:To observe the effect of Solitaire AB stent thrombectomy on the vascular endothelial function and inflammatory cytokines in patients with progressive cerebral infarction.Methods:A total of 58 patients with progressive cerebral infarction who were admitted in our hospital were included in the study and divided into the observation group and the control group according to different treatment protocols with 29 cases in each group. The patients in the control group were given the conservation treatment. On this basis, the patients in the observation group were given Solitaire AB stent thrombectomy. The changes of vascular endothelial function and inflammatory cytokines before and after treatment in the two groups were compared.Results:ET-1 after treatment in the two groups was significantly reduced, while NO and CGRP were significantly elevated when compared with before treatment (P<0.05). ET-1 after treatment in the observation group was significantly lower than that in the control group (P<0.05), while NO and CGRP were significantly higher than those in the control group (P<0.05). S100β protein, IL-6, TNF-α, hs-CRP, and MMP-9 levels after treatment in the two groups were significantly reduced when compared with before treatment (P<0.05). The above indicators after treatment in the observation group were significantly lower than those in the control group (P<0.05). MCA and ACA blood flow velocity after treatment in the two groups were significantly elevated when compared with before treatment (P<0.05). MCA and ACA blood flow velocity after treatment in the observation group were significantly higher than those in the control group (P<0.05).Conclusions:Solitaire AB stent thrombectomy can effectively reduce the inflammatory reaction in patients with progressive cerebral infarction, and improve the vascular endothelial function and blood supply for brain tissues.

  10. Exercise training normalizes skeletal muscle vascular endothelial growth factor levels in patients with essential hypertension

    DEFF Research Database (Denmark)

    Hansen, Ane Håkansson; Nielsen, Jens Jung; Saltin, Bengt;

    2010-01-01

    METHODS: Vascular endothelial growth factor (VEGF) protein and capillarization were determined in muscle vastus lateralis biopsy samples in individuals with essential hypertension (n = 10) and normotensive controls (n = 10). The hypertensive individuals performed exercise training for 16 weeks....... Muscle samples as well as muscle microdialysis fluid samples were obtained at rest, during and after an acute exercise bout, performed prior to and after the training period, for the determination of muscle VEGF levels, VEGF release, endothelial cell proliferative effect and capillarization. RESULTS...

  11. Leptin-induced transphosphorylation of vascular endothelial growth factor receptor increases Notch and stimulates endothelial cell angiogenic transformation.

    Science.gov (United States)

    Lanier, Viola; Gillespie, Corey; Leffers, Merle; Daley-Brown, Danielle; Milner, Joy; Lipsey, Crystal; Webb, Nia; Anderson, Leonard M; Newman, Gale; Waltenberger, Johannes; Gonzalez-Perez, Ruben Rene

    2016-10-01

    Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2). Interestingly, in the absence of VEGF, leptin induced the expression of several components of Notch signaling pathway in endothelial cells. Inhibition of VEGFR and Notch signaling significantly decreased leptin-induced S-phase progression, proliferation, and tube formation in endothelial cells. Moreover, leptin/OB-R induced transphosphorylation of VEGFR-1 and VEGFR-2 was essential for leptin's effects. These results unveil for the first time a novel mechanism by which leptin could induce angiogenic features via upregulation/trans-activation of VEGFR and downstream expression/activation of Notch in endothelial cells. Thus, high levels of leptin found in overweight and obese patients might lead to increased angiogenesis by activating VEGFR-Notch signaling crosstalk in endothelial cells. These observations might be highly relevant for obese patients with cancer, where leptin/VEGFR/Notch crosstalk could play an important role in cancer growth, and could be a new target for the control of tumor angiogenesis.

  12. Intracellular localization of lipoplexed siRNA in vascular endothelial cells of different mouse tissues.

    Science.gov (United States)

    Aleku, Manuela; Fisch, Gerald; Möpert, Kristin; Keil, Oliver; Arnold, Wolfgang; Kaufmann, Jörg; Santel, Ansgar

    2008-05-01

    Liposomally formulated siRNA can be used for RNAi applications in vivo. Intravenous bolus administration of lipoplexed siRNA has been shown to reduce gene expression in the vascular endothelium. Here, we applied immunofluorescence staining for different endothelial markers (PECAM-1, CD34, laminin) on paraffin sections to compare the respective expression pattern with the intracellular localization of intravenously administered, fluorescently labeled siRNA (siRNA-Cy3-lipoplex). By confocal microscopy, lipoplexed siRNA-Cy3 was detected inside vascular endothelial cells in vivo, which where identified with co-staining of endothelial markers. Consequently, the finding of intracellular siRNA uptake by vascular endothelial cells correlated with RNAi based specific protein reduction in situ as revealed by PECAM-1 specific immunofluorescence staining in lung tissue sections. Therefore, by using a cell biological approach these in situ data emphasize the functional uptake of liposomal siRNA molecules in vascular endothelial cells of different mouse tissues as indicated in our previous molecular study.

  13. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.

    Directory of Open Access Journals (Sweden)

    Mia Phillipson

    Full Text Available Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular and more rarely directly through endothelial cells (transcellular. Recently, we reported that unlike in wild-type (wt mice, Mac-1-/- (CD11b neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt. In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/- were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.

  14. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.

    Science.gov (United States)

    Phillipson, Mia; Kaur, Jaswinder; Colarusso, Pina; Ballantyne, Christie M; Kubes, Paul

    2008-02-20

    Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular) and more rarely directly through endothelial cells (transcellular). Recently, we reported that unlike in wild-type (wt) mice, Mac-1-/- (CD11b) neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt). In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/-) were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.

  15. Curcumin Attenuates Rapamycin-induced Cell Injury of Vascular Endothelial Cells.

    Science.gov (United States)

    Guo, Ning; Chen, Fangyuan; Zhou, Juan; Fang, Yuan; Li, Hongbing; Luo, Yongbai; Zhang, Yong

    2015-10-01

    Although drug-eluting stents (DES) effectively improve the clinical efficacy of percutaneous coronary intervention, a high risk of late stent thrombosis and in-stent restenosis also exists after DES implantation. Anti-smooth muscle proliferation drugs, such as rapamycin, coating stents, not only inhibit the growth of vascular smooth muscle cells but also inhibit vascular endothelial cells and delay the reendothelialization. Therefore, the development of an ideal agent that protects vascular endothelial cells from rapamycin-eluting stents is of great importance for the next generation of DES. In this study, we demonstrated that rapamycin significantly inhibited the growth of rat aortic endothelial cells in both dose- and time-dependent manner in vitro. Cell apoptosis was increased and migration was decreased by rapamycin treatments in rat aortic endothelial cells in vitro. Surprisingly, treatment with curcumin, an active ingredient of turmeric, significantly reversed these detrimental effects of rapamycin. Moreover, curcumin increased the expression of vascular nitric oxide synthases (eNOS), which was decreased by rapamycin. Furthermore, caveolin-1, the inhibitor of eNOS, was decreased by curcumin. Knockdown of eNOS by small interfering RNA significantly abrogated the protective effects of curcumin. Taken together, our results suggest that curcumin antagonizes the detrimental effect of rapamycin on aortic endothelial cells in vitro through upregulating eNOS. Therefore, curcumin is a promising combined agent for the rescue of DES-induced reendothelialization delay.

  16. 雌激素对绝经后女性冠心病患者血脂及血管内皮功能的影响%Effect of estrogen on blood lipid and vascular endothelial function of postmenopausal women with coronary heart disease

    Institute of Scientific and Technical Information of China (English)

    李彦芳; 吴媚; 赵彤

    2011-01-01

    目的:研究雌激素对绝经后女性冠心病患者血脂及血管内皮功能的影响,探讨绝经后女性冠心病患者血脂及血管内皮功能的相关性.方法:将60例绝经后女性冠心病患者随机分为治疗组和对照组各30例,治疗组在常规治疗的基础上服用尼尔雌醇2 mg,2周1次,对照组仅采用常规治疗,均连续服用6个月.于治疗前及治疗后检测血清总胆同醇(TC)、血清三酰甘油(TG)水平,低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)以及血浆内皮索(ET-1)和一氧化氮(NO)水平,并观察疗效.结果:①与治疗前相比,治疗组TC、TG、LDL-C、ET-1水平均明显下降,HDL-C、NO水平明显上升;②与对照组治疗后相比,治疗组TC、TG、ET-1水平均明显下降,HDL-C、NO水平明显上升,差异均有统计学意义(P<0.05);③Pearson相关分析显示,ET-1与TC、TG及LDL-C之间呈正相关,与HDL-C呈负相关;NO与TC、TG及LDL-C之间呈负相关,与HDL-C呈正相关,差异均有统计学意义(P<0.05).结论:血脂紊乱及血管内皮功能异常可能参与了绝经后女性冠心病的发生和发展,二者具有相关性;雌激素对绝经后冠心病患者的血脂有明显改善,并具有保护血管内皮功能的作用,有利于冠心病的防治.%Objective: To study the effect of estrogen on blood lipid and vascular endothelial function of postmenopausal women with coronary heart disease, explore the correlation between blood lipid and vascular endothelial function in postmenopausal women with coronary heart disease. Methods: 60 postmenopausal women with coronary heart disease were divided into treatment group and control group, 30 women in each group, the women in treatment group were treated with oral administration of nilestriol (2 mg) biweekly on the basis of routine treatment, while the women in control group were treated with routine treatment, all the women in the two groups were treated for 6 months.The serum levels of total

  17. Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function.

    Science.gov (United States)

    Hall, Wendy L

    2009-06-01

    The amount and type of dietary fat have long been associated with the risk of CVD. Arterial stiffness and endothelial dysfunction are important risk factors in the aetiology of CHD. A range of methods exists to assess vascular function that may be used in nutritional science, including clinic and ambulatory blood pressure monitoring, pulse wave analysis, pulse wave velocity, flow-mediated dilatation and venous occlusion plethysmography. The present review focuses on the quantity and type of dietary fat and effects on blood pressure, arterial compliance and endothelial function. Concerning fat quantity, the amount of dietary fat consumed habitually appears to have little influence on vascular function independent of fatty acid composition, although single high-fat meals postprandially impair endothelial function compared with low-fat meals. The mechanism is related to increased circulating lipoproteins and NEFA which may induce pro-inflammatory pathways and increase oxidative stress. Regarding the type of fat, cross-sectional data suggest that saturated fat adversely affects vascular function whereas polyunsaturated fat (mainly linoleic acid (18 : 2n-6) and n-3 PUFA) are beneficial. EPA (20 : 5n-3) and DHA (22 : 6n-3) can reduce blood pressure, improve arterial compliance in type 2 diabetics and dyslipidaemics, and augment endothelium-dependent vasodilation. The mechanisms for this vascular protection, and the nature of the separate physiological effects induced by EPA and DHA, are priorities for future research. Since good-quality observational or interventional data on dietary fatty acid composition and vascular function are scarce, no further recommendations can be suggested in addition to current guidelines at the present time.

  18. Vascular Endothelial Growth Factor-A Is Associated with Chronic Mountain Sickness in the Andean Population

    OpenAIRE

    Espinoza, Jose R.; Alvarez, Giancarlo; León-Velarde, Fabiola; Ju Preciado, Hugo F.; Macarlupu, Jose-Luis; Rivera-Ch, Maria; Rodriguez, Jorge; Favier, Judith; Gimenez-Roqueplo, Anne-Paule; Richalet, Jean-Paul

    2014-01-01

    Espinoza, Jose R., Giancarlo Alvarez, Fabiola León-Velarde, Hugo F. Ju Preciado, Jose-Luis Macarlupu, Maria Rivera-Ch, Jorge Rodriguez, Judith Favier, Anne-Paule Gimenez-Roqueplo, and Jean-Paul Richalet. Vascular endothelial growth factor-A is associated with chronic mountain sickness in Andean population. High Alt Med Biol. 15:146–154, 2014.—A study of chronic mountain sickness (CMS) with a candidate gene—vascular endothelial growth factor A (VEGFA)—was carried out in a Peruvian population l...

  19. The Role of Vitamin D in Blood Pressure, Endothelial and Renal Function in Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    Suzanne C. Ho

    2013-07-01

    Full Text Available Background: Vitamin D is a pro-hormone that plays an essential role in the vasculature and in kidney function. Aims: To review the extra-skeletal effects of vitamin D on blood pressure, endothelial and renal function with emphasis on recent findings in postmenopausal women. Methods: Included in this review was a PubMed database search for English language articles through March 2013. This review discussed the physiology and definition of vitamin D deficiency, the recent evidence for the role vitamin D in blood pressure, vascular and renal function. Results: Experimental and epidemiological data suggest that vitamin D plays an important role in the vasculature and in kidney function. Low vitamin D concentrations appear to significantly associate with hypertension, endothelial and renal dysfunction. However, the results of clinical trials have generally been mixed. Studies specifically conducted among postmenopausal women are limited and findings are still inconsistent. Conclusions: Definitive studies are warranted to elucidate the effects of vitamin D supplementation on vascular and renal function and a more detailed work is needed to outline the route, duration and optimal dose of supplementation. It is premature to recommend vitamin D as a therapeutic option in the improvement of vascular and renal function at the current stage.

  20. Cloning, large-scale production, and purification of active dimeric rat vascular endothelial growth factor (rrVEGF-164).

    NARCIS (Netherlands)

    Geutjes, P.J.; Nillesen, S.T.M.; Lammers, G.; Daamen, W.F.; Kuppevelt, A.H.M.S.M. van

    2010-01-01

    Large-scale production of recombinant rat vascular endothelial growth factor (rrVEGF-164) is desirable for angiogenic studies. In this study, biologically active recombinant rat vascular endothelial growth factor (rrVEGF-164) was cloned and expressed in the yeast Pichia pastoris, and large-scale pro

  1. Dysregulation of Vascular Endothelial Progenitor Cells Lung-Homing in Subjects with COPD

    Directory of Open Access Journals (Sweden)

    Brittany M. Salter

    2016-01-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is characterized by fixed airflow limitation and progressive decline of lung function and punctuated by occasional exacerbations. The disease pathogenesis may involve activation of the bone marrow stimulating mobilization and lung-homing of progenitor cells. We investigated the hypothesis that lower circulating numbers of vascular endothelial progenitor cells (VEPCs are a consequence of increased lung-sequestration in COPD. Nonatopic, current or ex-smokers with diagnosed COPD and nonatopic, nonsmoking normal controls were enrolled. Blood and induced sputum extracted primitive hemopoietic progenitors (HPCs and VEPC were enumerated by flow cytometry. Migration and adhesive responses to fibronectin were assessed. In sputum, VEPC numbers were significantly greater in COPD compared to normal controls. In blood, VEPCs were significantly lower in COPD versus normal controls. There were no differences in HPC levels between the two groups in either compartment. Functionally, there was a greater migrational responsiveness of progenitors from COPD subjects to stromal cell-derived factor-1alpha (SDF-1α compared to normal controls. This was associated with greater numbers of CXCR4+ progenitors in sputum from COPD. Increased migrational responsiveness of progenitor cells may promote lung-homing of VEPC in COPD which may disrupt maintenance and repair of the airways and contribute to COPD disease pathogenesis.

  2. Update on vascular endothelial Ca2+ signalling:A tale of ion channels,pumps and transporters

    Institute of Scientific and Technical Information of China (English)

    Francesco; Moccia; Roberto; Berra-Romani; Franco; Tanzi

    2012-01-01

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca2+ signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca2+ levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca2+ signals, ranging from brief, localized Ca2+ pulses to prolonged Ca2+ oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca2+ signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca2+ releasing channels, which arelocated both on the plasma membrane and in a number of intracellular organelles, and Ca2+ removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca2+ machinery in vascular ECs under both physiological and pathological conditions.

  3. Effects of Panax notoginseng saponins on vascular endothelial cells in vitro

    Institute of Scientific and Technical Information of China (English)

    關超然; 關加荤

    2000-01-01

    AIM: To investigate the inhibition of endothelium-dependent in vitro vascular relaxation induced by the total saponins (gensenosides) from Panax notoginseng ( PNS ) and the effect of PNS on the cytosolic Ca2 + concentration on cultured bovine pulmonary artery endothelial cells.METHODS: The endothelial-dependent vascular relaxation was assessed using acetylcholine (ACh) or cyclopiazonic acid (CPA) induced relaxation in endothelium-intact rat aorta. Cytosolic Caa + level was assessed in real time using dynamic digital fluorescence ratio imaging.RESULTS: In addition to its direct relaxation of the smooth muscle cells at high concentrations, PNS, at 100 mg/L having little effect on smooth muscle, caused a marked inhibition of endothelium-dependent relaxation brought about by PNS. This inhibitory effect was due to its inhibition of elevation of cytosolic Ca2 + , which is required for the activation of NO generation and release from the vascular endothelial cells. Nifedipine has no effect on either the endothelium-dependent relaxation or the cytosolic Ca2 + level in the cultured endothelial cells.CONCLUSION: Our findings are consistent with the known action of PNS on receptor-operated Ca2 + channels and support our contention that PNS inhibits endotheliumdependent relaxation by preventing the increase of Ca2 + level in endothelial cells via the receptor-operated Ca2 + channels in the presence of ACh or the non-selective cation channels opened by CPA.

  4. Relationship between dyslipidemia and vascular endothelial function in patients with coronary artery spasm

    Institute of Scientific and Technical Information of China (English)

    向定成

    2006-01-01

    Objectives To investigate the effects of dyslipidemia on vascular endothelial function in patients with coronary artery spasm. Methods Sixty-four patients with chest pain but without significant angiographic stenosis were divided into coronary spasm group (n=46 with coronary spasm) and control group (n=18 without coronary spasm) according to acetylcholine provoking test. Endothelin-1 (ET-1), nitric oxide (NO) and lipids were

  5. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors.

    NARCIS (Netherlands)

    Kruser, T.J.; Wheeler, D.L.; Armstrong, E.A.; Iida, M.; Kozak, K.R.; Kogel, A.J. van der; Bussink, J.; Coxon, A.; Polverino, A.; Harari, P.M.

    2010-01-01

    BACKGROUND: Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between motesanib and radiation in vitro and in head and neck squamous cell carcinoma

  6. Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

    2010-01-01

    OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe...... levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes....

  7. Subcellular localization and mechanism of secretion of vascular endothelial growth factor in human skeletal muscle

    DEFF Research Database (Denmark)

    Høier, Birgitte; Prats Gavalda, Clara; Qvortrup, Klaus;

    2013-01-01

    The subcellular distribution and secretion of vascular endothelial growth factor (VEGF) was examined in skeletal muscle of healthy humans. Skeletal muscle biopsies were obtained from m.v. lateralis before and after a 2 h bout of cycling exercise. VEGF localization was conducted on preparations...

  8. RNA interference inhibits expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial cells

    Institute of Scientific and Technical Information of China (English)

    CAI Chun-mei; SUN Bao-chen; LIU Xu-yang; WANG Jin-jin; LI Jun-fa; HAN Song; WANG Ning-li; LU Qing-jun

    2005-01-01

    @@ Choroidal neovascularization (CNV), a major cause of vision loss, is the result of the increased vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. It is important to inhibit the expression of VEGF protein in RPE cells.

  9. Tumor MMP-1 Activates Endothelial PAR1 to Facilitate Vascular Intravasation and Metastatic Dissemination

    DEFF Research Database (Denmark)

    Juncker-Jensen, Anna; Deryugina, Elena I; Rimann, Ivo

    2013-01-01

    non-tumor-cell/non-matrix target, activation of which by carcinoma-produced MMP-1 regulates endothelial permeability and transendothelial migration. The inhibitory effects of specific PAR1 antagonists in live animals have also indicated that the mechanisms of MMP-1-dependent vascular permeability...

  10. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells.

    Science.gov (United States)

    Warnock, David G; Kusche-Vihrog, Kristina; Tarjus, Antoine; Sheng, Shaohu; Oberleithner, Hans; Kleyman, Thomas R; Jaisser, Frederic

    2014-03-01

    Sodium transport in the distal nephron is mediated by epithelial sodium channel activity. Proteolytic processing of external domains and inhibition with increased sodium concentrations are important regulatory features of epithelial sodium channel complexes expressed in the distal nephron. By contrast, sodium channels expressed in the vascular system are activated by increased external sodium concentrations, which results in changes in the mechanical properties and function of endothelial cells. Mechanosensitivity and shear stress affect both epithelial and vascular sodium channel activity. Guyton's hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. The synergistic effects, and complementary regulation, of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and probably reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. In this Review, we focus on the expression and regulation of sodium channels, and we outline the emerging evidence that describes the central role of amiloride-sensitive sodium channels in the efferent (vascular) and afferent (epithelial) arms of this homeostatic system.

  11. Expression of vascular endothelial growth factor and its two receptors in normal human endometrium

    Institute of Scientific and Technical Information of China (English)

    王海燕; 陈贵安

    2003-01-01

    Objectives: We try to demonstrate the expression of vascular endothelial growthfactor (VEGF) and its receptors, flt-1 and KDR, in normal human emdometrium duringthe menstrual cycle.Methods: Immunohistochemical method was used to observe the expression ofVEGF and its two receptors in emdometrium throughout the normal menstrual cyclemeanwhile the isoforms of VEGF were also detected by Western blot analysis. The en-dothelial cells of micro-vessels were marked with Ⅷ factor antibody.Results: VEGF and its receptors existed in endometrial glandular, stromal and vas-cular endothelial cells of human endometrium. Their expressions were higher in the mid-secretory phase of menstrual cycle and highest at menstruation. VEGF121 and VEGF165were the predominant isoforms in normal human endometrium.Conclusion: The expression of VEGF and its two receptors showed cycle-dependentin human endometrium, probably involved in embryonic implantation and endometrialproliferation and differentiation.

  12. [Biological activities of exogenous polysaccharides via controlling endogenous proteoglycan metabolism in vascular endothelial cells].

    Science.gov (United States)

    Sato, Tomoko; Yamamoto, Chika; Fujiwara, Yasuyuki; Kaji, Toshiyuki

    2008-05-01

    Proteoglycan contains glycosmainoglycans, which are endogenous sulfated polysaccharides, in the molecule. The metabolism of proteoglycans regulates cell behavior and cellular events. It is possible that exogenous polysaccharide-related molecules exhibit their biological activities by two mechanisms. One is the interaction with cells and the other is the interaction with growth factors/cytokines that regulate proteoglycans. In this review, we describe sodium spirulan, a sulfated polysaccharide obtained from a hot-water extract of the blue-green alga Spirulina platensis, as an exogenous polysaccharide that stimulates the release of proteoglycans from vascular endothelial cells. Factors that regulate endothelial proteoglycan metabolism are also being described as possible target molecules of exogenous polysaccharides. Further research is required to obtain exogenous polysaccharide-related molecules that exhibit useful biological activities through controlling endothelial proteoglycan metabolism for protection against vascular lesions such as atheroslcerosis.

  13. SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells.

    Science.gov (United States)

    Li, Yanxiang; Wang, Ping; Yang, Xiaofeng; Wang, Weirong; Zhang, Jiye; He, Yanhao; Zhang, Wei; Jing, Ting; Wang, Bo; Lin, Rong

    2016-09-01

    Emerging evidence has indicated that vascular endothelial cells (ECs) not only form the barrier between blood and the vessel wall but also serve as conditional innate immune cells. Our previous study found that SIRT1, a class III histone deacetylase, inhibits the inflammatory response in ECs. Recent studies revealed that SIRT1 also participates in the modulation of immune responses. Although the NLRP3 inflammasome is known to be a crucial component of the innate immune system, there is no direct evidence demonstrating the anti-inflammatory effect of SIRT1 on ECs through the NLRP3 inflammasome. In this study, we observed that lipopolysaccharide (LPS) and adenosine triphosphate (ATP) triggered the activation of NLRP3 inflammasome in human umbilical vein ECs (HUVECs). Moreover, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in significant increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. Importantly, the lack of SIRT1 enhanced NLRP3 inflammasome activation and subsequent caspase-1 cleavage. On the other hand, NLRP3 siRNA blocked the activation of the NLRP3 inflammasome in HUVECs stimulated with LPS plus ATP. Further study revealed that NLRP3 inflammasome blockade significantly reduced MCP-1 and CRP production in HUVECs. In vivo studies indicated that implantation of the periarterial carotid collar inhibited arterial SIRT1 expression in rabbits. Meanwhile, treatment with a SIRT1 activator decreased the expression levels of MCP-1 and CRP in collared arteries and the interleukin (IL)-1β level in serum. Taken together, these findings indicate that NLRP3 inflammasome activation promoted endothelial inflammation and that SIRT1 inhibits the inflammatory response partly through regulation of the NLRP3 inflammasome in ECs.

  14. Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Lixue Dong

    2017-01-01

    Full Text Available Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”, and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4 is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs. We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER stress response genes such as CHOP (C/EBP homologous protein and ATF3 (activating transcription factor 3. In the current study, we have examined acidosis/GPR4- induced ER stress pathways in human umbilical vein endothelial cells (HUVEC and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α, phosphorylated IRE1α (inositol-requiring enzyme 1α, and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1, was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic

  15. Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Cheng-Jui Lin

    2016-12-01

    Full Text Available Background/Aims: Indoxyl sulfate (IS is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease (CKD. We explored the effect of IS on human early endothelial progenitor cells (EPCs and analyzed the correlation between serum IS levels and parameters of vascular function, including endothelial function in a CKD-based cohort. Methods: A cross-sectional study with 128 stable CKD patients was conducted. Flow-mediated dilation (FMD, pulse wave velocity (PWV, ankle brachial index, serum IS and other biochemical parameters were measured and analyzed. In parallel, the activity of early EPCs was also evaluated after exposure to IS. Results: In human EPCs, a concentration-dependent inhibitory effect of IS on chemotactic motility and colony formation was observed. Additionally, serum IS levels were significantly correlated with CKD stages. The total IS (T-IS and free IS (F-IS were strongly associated with age, hypertension, cardiovascular disease, blood pressure, PWV, blood urea nitrogen, creatine and phosphate but negatively correlated with FMD, the estimated glomerular filtration rate (eGFR, hemoglobin, hematocrit, and calcium. A multivariate linear regression analysis also showed that FMD was significantly associated with IS after adjusting for other confounding factors. Conclusions: In humans, IS impairs early EPCs and was strongly correlated with vascular dysfunction. Thus, we speculate that this adverse effect of IS may partly result from the inhibition of early EPCs.

  16. Identification of nitric oxide as an endogenous inhibitor of 26S proteasomes in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Hongtao Liu

    Full Text Available The 26S proteasome plays a fundamental role in almost all eukaryotic cells, including vascular endothelial cells. However, it remains largely unknown how proteasome functionality is regulated in the vasculature. Endothelial nitric oxide (NO synthase (eNOS-derived NO is known to be essential to maintain endothelial homeostasis. The aim of the present study was to establish the connection between endothelial NO and 26S proteasome functionality in vascular endothelial cells. The 26S proteasome reporter protein levels, 26S proteasome activity, and the O-GlcNAcylation of Rpt2, a key subunit of the proteasome regulatory complex, were assayed in 26S proteasome reporter cells, human umbilical vein endothelial cells (HUVEC, and mouse aortic tissues isolated from 26S proteasome reporter and eNOS knockout mice. Like the other selective NO donors, NO derived from activated eNOS (by pharmacological and genetic approach increased O-GlcNAc modification of Rpt2, reduced proteasome chymotrypsin-like activity, and caused 26S proteasome reporter protein accumulation. Conversely, inactivation of eNOS reversed all the effects. SiRNA knockdown of O-GlcNAc transferase (OGT, the key enzyme that catalyzes protein O-GlcNAcylation, abolished NO-induced effects. Consistently, adenoviral overexpression of O-GlcNAcase (OGA, the enzyme catalyzing the removal of the O-GlcNAc group, mimicked the effects of OGT knockdown. Finally, compared to eNOS wild type aortic tissues, 26S proteasome reporter mice lacking eNOS exhibited elevated 26S proteasome functionality in parallel with decreased Rpt2 O-GlcNAcylation, without changing the levels of Rpt2 protein. In conclusion, the eNOS-derived NO functions as a physiological suppressor of the 26S proteasome in vascular endothelial cells.

  17. Effects of tempol on endothelial and vascular dysfunctions and insulin resistance induced by a high-fat high-sucrose diet in the rat.

    Science.gov (United States)

    Bourgoin, Frédéric; Bachelard, Hélène; Badeau, Mylène; Larivière, Richard; Nadeau, André; Pitre, Maryse

    2013-07-01

    We investigated the effects of treatment with tempol (an antioxidant) on vascular and metabolic dysfunction induced by a high-fat high-sucrose (HFHS) diet. Rats were randomized to receive an HFHS or chow diet with or without tempol treatment (1.5 mmol·(kg body mass)(-1)·day(-1)) for 4 weeks. Blood pressure, heart rate, and blood flow were measured in the rats by using intravascular catheters and Doppler flow probes. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic-hyperinsulinemic clamp. In-vitro studies were performed to evaluate vascular reactivity and endothelial and inducible nitric oxide synthase (eNOS; iNOS) expression in vascular and muscle tissues. Endothelin, nitrotyrosine, and NAD(P)H oxidase expressions were determined in vascular tissues, and glucose transport activity and glucose transporter 4 (GLUT4) expression were examined in muscles. Tempol treatment was found to prevent alterations in insulin sensitivity, glucose transport activity, GLUT4 expression, and vascular reactivity, and to prevent increases in plasma insulin, blood pressure, and heart rate noted in the untreated HFHS-fed rats. These were associated with increased levels of eNOS expression in vascular and muscle tissues, but reductions in nitrotyrosine, endothelin, NAD(P)H oxidase, and iNOS expressions. Therefore, oxidative stress induced by a relatively short-term HFHS diet could contribute to the early development of vascular and metabolic abnormalities in rats.

  18. Post-weaning protein malnutrition increases blood pressure and induces endothelial dysfunctions in rats.

    Science.gov (United States)

    de Belchior, Aucelia C S; Angeli, Jhuli K; Faria, Thaís de O; Siman, Fabiana D M; Silveira, Edna A; Meira, Eduardo F; da Costa, Carlos P; Vassallo, Dalton V; Padilha, Alessandra S

    2012-01-01

    Malnutrition during critical periods in early life may increase the subsequent risk of hypertension and metabolic diseases in adulthood, but the underlying mechanisms are still unclear. We aimed to evaluate the effects of post-weaning protein malnutrition on blood pressure and vascular reactivity in aortic rings (conductance artery) and isolated-perfused tail arteries (resistance artery) from control (fed with Labina®) and post-weaning protein malnutrition rats (offspring that received a diet with low protein content for three months). Systolic and diastolic blood pressure and heart rate increased in the post-weaning protein malnutrition rats. In the aortic rings, reactivity to phenylephrine (10(-10)-3.10(-4) M) was similar in both groups. Endothelium removal or L-NAME (10(-4) M) incubation increased the response to phenylephrine, but the L-NAME effect was greater in the aortic rings from the post-weaning protein malnutrition rats. The protein expression of the endothelial nitric oxide isoform increased in the aortic rings from the post-weaning protein malnutrition rats. Incubation with apocynin (0.3 mM) reduced the response to phenylephrine in both groups, but this effect was higher in the post-weaning protein malnutrition rats, suggesting an increase of superoxide anion release. In the tail artery of the post-weaning protein malnutrition rats, the vascular reactivity to phenylephrine (0.001-300 µg) and the relaxation to acetylcholine (10(-10)-10(-3) M) were increased. Post-weaning protein malnutrition increases blood pressure and induces vascular dysfunction. Although the vascular reactivity in the aortic rings did not change, an increase in superoxide anion and nitric oxide was observed in the post-weaning protein malnutrition rats. However, in the resistance arteries, the increased vascular reactivity may be a potential mechanism underlying the increased blood pressure observed in this model.

  19. Post-weaning protein malnutrition increases blood pressure and induces endothelial dysfunctions in rats.

    Directory of Open Access Journals (Sweden)

    Aucelia C S de Belchior

    Full Text Available Malnutrition during critical periods in early life may increase the subsequent risk of hypertension and metabolic diseases in adulthood, but the underlying mechanisms are still unclear. We aimed to evaluate the effects of post-weaning protein malnutrition on blood pressure and vascular reactivity in aortic rings (conductance artery and isolated-perfused tail arteries (resistance artery from control (fed with Labina® and post-weaning protein malnutrition rats (offspring that received a diet with low protein content for three months. Systolic and diastolic blood pressure and heart rate increased in the post-weaning protein malnutrition rats. In the aortic rings, reactivity to phenylephrine (10(-10-3.10(-4 M was similar in both groups. Endothelium removal or L-NAME (10(-4 M incubation increased the response to phenylephrine, but the L-NAME effect was greater in the aortic rings from the post-weaning protein malnutrition rats. The protein expression of the endothelial nitric oxide isoform increased in the aortic rings from the post-weaning protein malnutrition rats. Incubation with apocynin (0.3 mM reduced the response to phenylephrine in both groups, but this effect was higher in the post-weaning protein malnutrition rats, suggesting an increase of superoxide anion release. In the tail artery of the post-weaning protein malnutrition rats, the vascular reactivity to phenylephrine (0.001-300 µg and the relaxation to acetylcholine (10(-10-10(-3 M were increased. Post-weaning protein malnutrition increases blood pressure and induces vascular dysfunction. Although the vascular reactivity in the aortic rings did not change, an increase in superoxide anion and nitric oxide was observed in the post-weaning protein malnutrition rats. However, in the resistance arteries, the increased vascular reactivity may be a potential mechanism underlying the increased blood pressure observed in this model.

  20. Extra-vascular type of oral intravascular papillary endothelial hyperplasia (Masson′s tumor of lower lip: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    G S Sarode

    2015-01-01

    Full Text Available Intravascular papillary endothelial hyperplasia (IPEH is an unusual reactive lesion of vascular origin, which rarely occurs in the oral cavity. Pathogenetically, is it divided into true, mixed and extra-vascular types. We report a case of extra-vascular IPEH of the lower lip in 54-year-old female patient. Patient gives history of trauma 4 months back with lesion developing at the site to trauma. The lesion was 3 cm × 4 cm in size with soft to firm in consistency. Histologically, it is characterized by an exuberant papillary endothelial cell proliferation toward the lumen of an enlarged blood vessel from the area of an organizing thrombus. The lesion was surgically excised under local anesthesia. The patient was followed for 1-year with no evidence of recurrence. This paper discusses the various aspects of IPEH of the oral cavity such as pathogenesis, clinical features, histopathology treatment, and prognosis.

  1. Construction and characterization of osteogenic and vascular endothelial cell sheets from rat adipose-derived mesenchymal stem cells.

    Science.gov (United States)

    Zhang, Hualin; Yu, Na; Zhou, Yueli; Ma, Hairong; Wang, Juan; Ma, Xuerong; Liu, Jinsong; Huang, Jin; An, Yilin

    2016-10-01

    In this study, adipose-derived mesenchymal stem cells (ADSCs) were isolated from adipose tissues of rats. Flow cytometry identification showed that ADSCs of passage 3 highly expressed CD29 and CD44, but hardly expressed CD31 and CD45. Adipogenic, osteogenic, and chondrogenic differentiation were confirmed by the results of oil red O staining, alkaline phosphatase (ALP), and alcian blue staining, respectively. ADSCs at a density of 1×10(6)/cm(2) were cultured in the osteogenic medium and the osteogenic cell sheets could be obtained after 14 d. The cell sheets were positive with von kossa staining. The transmission electron microscopy (TEM) result showed that needle-like calcium salt crystals were deposited on the ECM. These results suggested that the osteogenic cell sheets may have potential osteogenesis ability. ADSCs at a density of 1×10(6)/cm(2) were cultured in the endothelial cell growth medium-2 and the endothelial cell sheets can be formed after 16 d of culture. The TEM image confirmed that the Weibel-Palade corpuscle was seen in the cells. The expression of CD31 was positive, suggesting that the endothelial cell sheets may have a strong ability to form blood vessels. In this study, two types of cell sheets with the potential abilities of osteogenesis and blood vessels formation were obtained by induced culture of ADSCs in vitro, which lays a foundation to build vascularized tissue engineered bone for the therapy of bone defects.

  2. Tissue engineering of urethra using human vascular endothelial growth factor gene-modified bladder urothelial cells.

    Science.gov (United States)

    Guan, Yong; Ou, Lailiang; Hu, Gang; Wang, Hongjun; Xu, Yong; Chen, Jiatong; Zhang, Jun; Yu, Yaoting; Kong, Deling

    2008-02-01

    Acquired or congenital abnormalities may lead to urethral damage or loss, often requiring surgical reconstruction. Urethrocutaneous fistula and strictures are common complications, due to inadequate blood supply. Thus, adequate blood supply is a key factor for successful urethral tissue reconstruction. In this study, urethral grafts were prepared by seeding rabbit bladder urothelial cells (UCs) modified with human vascular endothelial growth factor (VEGF(165)) gene in the decellularized artery matrix. A retroviral pMSCV-VEGF(165)-GFP vector was cloned by insertion of VEGF open reading frame into the vector pMSCV-GFP (murine stem cell virus [MSCV]; green fluorescent protein [GFP]). Retrovirus was generated using package cell line 293T. Rabbit UCs were expanded ex vivo and modified with either MSCV-VEGF(165)-GFP or control MSCV-GFP retrovirus. Transduction efficiency was analyzed by fluorescence-activated cell sorting. The expression of VEGF(165) was examined by immunofluorescence, reverse transcript-polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay (ELISA). Decellularized rabbit artery matrix was seeded with genetically modified UCs and was subsequently cultured for 1 week prior to subcutaneous implantation into nude mice. Four weeks after implantation, the implants were harvested and analyzed by fluorescence microscopy, and by histologic and immunohistochemical staining. Ex vivo transduction efficiency of UCs was greater than 50% when concentrated retrovirus was used. The modified cells expressed both VEGF and GFP protein. Furthermore, the VEGF-modified UCs secreted VEGF in a time-dependent manner. Scanning electron microscopy and histochemical analysis of cross sections of the cultured urethral grafts showed that the seeded cells were attached and proliferated on the luminal surface of the decellularized artery matrix. In the subcutaneously implanted vessels, VEGF-modified cells significantly enhanced neovascularization and the

  3. Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis.

    Science.gov (United States)

    Miller, Daniel; Forrester, Kevin; Hart, David A; Leonard, Catherine; Salo, Paul; Bray, Robert C

    2007-03-01

    Chronic inflammation associated with osteoarthritis (OA) may alter normal vascular responses and contribute to joint degradation. Vascular responses to vasoactive mediators were evaluated in the medial collateral ligament (MCL) of the anterior cruciate ligament (ACL)-deficient knee. Chronic joint instability and progressive OA were induced in rabbit knees by surgical transection of the ACL. Under halothane anesthesia, laser speckle perfusion imaging (LSPI) was used to measure MCL blood flow in unoperated control (n = 12) and 6-wk ACL-transected knees (n = 12). ACh, bradykinin, histamine, substance P (SP), and prostaglandin E(2) (PGE(2)) were applied to the MCL vasculature in topical boluses of 100 microl (dose range 10(-14) to 10(-8) mol). In normal joints, ACh, bradykinin, histamine, and PGE(2) evoked a dilatory response. Substance P caused a biphasic response that was dilatory from 10(-14) to 10(-11) mol and constricting at higher doses. In ACL-deficient knees, ACh, bradykinin, histamine, and SP decreased perfusion, whereas PGE(2) had a biphasic response that decreased perfusion at 10(-14) to 10(-11) mol and was dilatory at higher concentrations. Sodium nitroprusside increased perfusion in resting and phenylephrine-precontracted vessels with no significant differences between ACL-transected and control knees. Femoral artery occlusion and release increased perfusion by 74.3 +/- 11.1% in control knees but only by 25.8 +/- 4.4% in ACL-deficient knees. The altered responsiveness of the MCL vasculature to these inflammatory mediators may indicate endothelial dysfunction in the MCL, which may contribute to the progression and severity of OA and to the adaptation of the joint in an altered mechanical environment.

  4. Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders.

    Directory of Open Access Journals (Sweden)

    Johanna M Walz

    Full Text Available Vascular endothelial growth factor-A (VEGF-A is intensively investigated in various medical fields. However, comparing VEGF-A measurements is difficult because sample acquisition and pre-analytic procedures differ between studies. We therefore investigated which variables act as confounders of VEGF-A measurements.Following a standardized protocol, blood was taken at three clinical sites from six healthy participants (one male and one female participant at each center twice one week apart. The following pre-analytical parameters were varied in order to analyze their impact on VEGF-A measurements: analyzing center, anticoagulant (EDTA vs. PECT / CTAD, cannula (butterfly vs. neonatal, type of centrifuge (swing-out vs. fixed-angle, time before and after centrifugation, filling level (completely filled vs. half-filled tubes and analyzing method (ELISA vs. multiplex bead array. Additionally, intrapersonal variations over time and sex differences were explored. Statistical analysis was performed using a linear regression model.The following parameters were identified as statistically significant independent confounders of VEGF-A measurements: analyzing center, anticoagulant, centrifuge, analyzing method and sex of the proband. The following parameters were no significant confounders in our data set: intrapersonal variation over one week, cannula, time before and after centrifugation and filling level of collection tubes.VEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples.

  5. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration in a Turkish population

    Institute of Scientific and Technical Information of China (English)

    Yunus; Bulgu; Gokhan; Ozan; Cetin; Vildan; Caner; Ebru; Nevin; Cetin; Volkan; Yaylali; Cem; Yildirim

    2014-01-01

    AIM:To assess the association between age-related macular degeneration(AMD) and three single nucleotide polymorphisms(SNPS) related to the vascular endothelial growth factor(VEGF) gene.METHODS:The patients who were diagnosed with AMD were included in this prospective study. Three SNPs(rs1413711, rs2146323, and rs3025033) of the VEGF gene were genotyped by real-time polymerase chain reaction in the genomic DNA isolated from peripheral blood samples of the 82 patients and 80 controls.RESULTS:The genotype frequencies of rs1413711 and rs2146323 were not significantly different between the study group and the control group(P =0.072 and P =0.058).However, there was a significant difference in the genotype frequencies of these SNPs between the wet type AMD and dry type AMD(P =0.005 and P =0.010,respectively). One of the SNPs(rs1413711) was also found to be associated with the severity of AMD(P =0.001)with significant genotype distribution between early,intermediate, and advanced stages of the disease. The ancestral alleles were protective for both SNPs while the polymorphic alleles increased the risk for dry AMD.CONCLUSION:VEGF SNPs rs1413711 and rs2146323 polymorphisms are significantly associated with AMD subtypes in our population.

  6. Acceleration of Medpor implant fibrovascularization with local vascular endothelial growth-factor injections: An experimental study

    Directory of Open Access Journals (Sweden)

    Mert Demirel

    2015-12-01

    Full Text Available Objective: Medpor is a biocompatible, high-density porous polyethylene implant that is used for multiple indications in plastic surgery. The most frequent complications associated with the Medpor implant are infection and implant exposure. The primary cause of these complications is poor fibrovascularization of the Medpor implant and poor nourishment of the overlying skin. The present experimental study aimed to determine whether vascular endothelial growth factor (VEGF could accelerate and increase Medpor implant fibrovascularization in vivo, and thereby improve local nourishment and prevent complications. Materials and Methods: The Medpor implant was inserted under the dorsal skin area in 40 Sprague-Dawley rats. 20 rats receiving local VEGF injections comprised the study group. The control group received saline injections. Fibrovascularization of the Medpor implants was compared. Results: In the rats injected with VEGF, the Medpor implant fibrovascularized faster, and there were more newly formed blood vessels, as compared with those in the control group. Conclusion: These findings have led to our use of VEGF-like agents that the accelerate angiogenesis in the Medpor implant as a means to reduce the incidence of such complications as infection and implant exposure. [Arch Clin Exp Surg 2015; 4(4.000: 196-201

  7. A novel approach to the assessment of vascular endothelial function

    Energy Technology Data Exchange (ETDEWEB)

    Sathasivam, S; Siddiqui, Z; Greenwald, S [Pathology Group, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (United Kingdom); Phababpha, S; Sengmeuan, P; Detchaporn, P; Kukongviriyapan, U, E-mail: s.e.greenwald@qmul.ac.uk [Department of Physiology, Khon Kaen University, Khon Kaen (Thailand)

    2011-08-17

    Impaired endothelial function (EF) is associated with atherogenesis, and its quantitative assessment has prognostic value. Currently, methods based on assessing flow-mediated dilation (FMD) are technically difficult and expensive. We tested a novel way of assessing EF by measuring the time difference between pulses arriving at the middle fingers of each hand (f-f{Delta}T), whilst FMD is induced in one arm. We compared f-f{Delta}T with standard methods in healthy and diseased subjects. Our findings suggest that the proposed simple and inexpensive technique gives comparable results and has the potential to qualitatively assess EF in the clinical setting, although further work is required.

  8. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Pei-Lin, E-mail: pchen@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Easton, Alexander S., E-mail: alexander.easton@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    2010-01-01

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10{sup -5} mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  9. The role of shear stress in Blood-Brain Barrier endothelial physiology

    Directory of Open Access Journals (Sweden)

    Puvenna Vikram

    2011-05-01

    Full Text Available Abstract Background One of the most important and often neglected physiological stimuli contributing to the differentiation of vascular endothelial cells (ECs into a blood-brain barrier (BBB phenotype is shear stress (SS. With the use of a well established humanized dynamic in vitro BBB model and cDNA microarrays, we have profiled the effect of SS in the induction/suppression of ECs genes and related functions. Results Specifically, we found a significant upregulation of tight and adherens junctions proteins and genes. Trans-endothelial electrical resistance (TEER and permeability measurements to know substances have shown that SS promoted the formation of a tight and highly selective BBB. SS also increased the RNA level of multidrug resistance transporters, ion channels, and several p450 enzymes. The RNA level of a number of specialized carrier-mediated transport systems (e.g., glucose, monocarboxylic acid, etc. was also upregulated. RNA levels of modulatory enzymes of the glycolytic pathway (e.g., lactate dehydrogenase were downregulated by SS while those involved in the Krebs cycle (e.g., lactate and other dehydrogenases were upregulated. Measurements of glucose consumption versus lactate production showed that SS negatively modulated the glycolytic bioenergetic pathways of glucose metabolism in favor of the more efficient aerobic respiration. BBB ECs are responsive to inflammatory stimuli. Our data showed that SS increased the RNA levels of integrins and vascular adhesion molecules. SS also inhibited endothelial cell cycle via regulation of BTG family proteins encoding genes. This was paralleled by significant increase in the cytoskeletal protein content while that of membrane, cytosol, and nuclear sub-cellular fractions decreased. Furthermore, analysis of 2D gel electrophoresis (which allows identifying a large number of proteins per sample of EC proteins extracted from membrane sub-cellular endothelial fractions showed that SS increased

  10. Correlation of CD105 and Vascular Endothelial Growth Factor in Laser-induced Choroidal Neovascularization in Rats

    Institute of Scientific and Technical Information of China (English)

    Jianfeng Xu; Yusheng Wang; Xiumei Yang; Peng Zhang; Lijun Chen

    2006-01-01

    Purpose: Choroidal neovascularization (CNV) plays an important role in pathogenesis of age-related macular degeneration (AMD), ocular histoplasmosis syndrome (OHS) and so on. However, mechanisms of CNV formation are not fully understood. The aim of this study is to investigate the correlation between expressions of CD105 and vascular endothelial growth factor (VEGF) in experimental laserinduced CNV in rats.Methods: CNV model was established by 532 nm laser photocoagulation in BrownNorway rats. The expression of CD105 and VEGF in CNV was observed by immunohistochemistry at 3, 7, 14, 21, 28 and 56 days after laser photocoagulation.The image analysis was performed with the professional software of Image-Pro Plus.Results: Fluorescein angiography showed fluorescein leakage in CNV from days 7 to 56 after photocoagulation. VEGF expression was mainly observed in vascular endothelial cells, ganglion cells, inner nuclear layers and retinal pigment epithelial cells in normal retina and vascular endothelial cells in normal choroid of the rats. On day 3 after photocoagulation, VEGF began to express in laser-induced lesions. VEGF was strongly expressed in CNV after 7 days (P<0.05) and decreased after 14 days (P>0.05). CD105 was initially presented in CNV at 7 days and obviously expressed at 14 days after photocoagulation (P<0.05). Four weeks later, when angiogenesis tended toward inactive status, expression of CD 105 was markedly decreased (P>0.05).There was notablely direct correlation between CD105-positive-microvessel density and positively semiquantitative scoring of VEGF in the CNV(r=0.989, P<0.01).Conclusions: There is direct correlation between the expression of CD105 and VEGF in the laser-induced CNV in rat. It suggests that CD105 and VEGF might participate in the new blood vessel formation and promote the growth of CNV.

  11. Vascular Response to Graded Angiotensin II Infusion in Offspring Subjected to High-Salt Drinking Water during Pregnancy: The Effect of Blood Pressure, Heart Rate, Urine Output, Endothelial Permeability, and Gender

    OpenAIRE

    2014-01-01

    Introduction. Rennin-angiotensin system and salt diet play important roles in blood pressure control. We hypothesized that the high-salt intake during pregnancy influences the degree of angiotensin-dependent control of the blood pressure in adult offspring. Methods. Female Wistar rats in two groups (A and B) were subjected to drink tap and salt water, respectively, during pregnancy. The offspring were divided into four groups as male and female offspring from group A (groups 1 and 2) and from...

  12. Engineering interaction between bone marrow derived endothelial cells and electrospun surfaces for artificial vascular graft applications.

    Science.gov (United States)

    Ahmed, Furqan; Dutta, Naba K; Zannettino, Andrew; Vandyke, Kate; Choudhury, Namita Roy

    2014-04-14

    The aim of this investigation was to understand and engineer the interactions between endothelial cells and the electrospun (ES) polyvinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) nanofiber surfaces and evaluate their potential for endothelialization. Elastomeric PVDF-HFP samples were electrospun to evaluate their potential use as small diameter artificial vascular graft scaffold (SDAVG) and compared with solvent cast (SC) PVDF-HFP films. We examined the consequences of fibrinogen adsorption onto the ES and SC samples for endothelialisation. Bone marrow derived endothelial cells (BMEC) of human origin were incubated with the test and control samples and their attachment, proliferation, and viability were examined. The nature of interaction of fibrinogen with SC and ES samples was investigated in detail using ELISA, XPS, and FTIR techniques. The pristine SC and ES PVDF-HFP samples displayed hydrophobic and ultrahydrophobic behavior and accordingly, exhibited minimal BMEC growth. Fibrinogen adsorbed SC samples did not significantly enhance endothelial cell binding or proliferation. In contrast, the fibrinogen adsorbed electrospun surfaces showed a clear ability to modulate endothelial cell behavior. This system also represents an ideal model system that enables us to understand the natural interaction between cells and their extracellular environment. The research reported shows potential of ES surfaces for artificial vascular graft applications.

  13. Production of neutralizing monoclonal antibody against human vascular endothelial growth factor receptor Ⅱ

    Institute of Scientific and Technical Information of China (English)

    Rong LI; Dong-sheng XIONG; Xiao-feng SHAO; Jia LIU; Yuan-fu XU; Yuan-sheng XU; Han-zhi LIU; Zhen-ping ZHU; Chun-zheng YANG

    2004-01-01

    AIM: To prepare neutralizing monoclonal antibody (mAb) against extracellular immunoglobulin (Ig)-like domainⅢ of vascular endothelial growth factor receptor KDR and study its biological activity. METHODS: Soluble KDR Ig domain Ⅲ (KDR-Ⅲ) fusion protein was expressed in E Coli and purified from the bacterial periplasmic extracts via an affinity chromatography. Monoclonal antibodies against KDR-Ⅲ were prepared by hybridoma technique. ELISA and FACS analysis were used to identify its specificity. Immunoprecipitation and [3H]-thymidine incorporation assay were also used to detect the activity of anti-KDR mAb blocking the phosphorylation of KDR tyrosine kinase receptor and the influence on vascular endothelial growth factor-induced mitogenesis of human endothelial ceils.RESULTS: A monoclonal antibody, Ycom1D3 (IgG1), was generated from a mouse immunized with the recombinant KDR-Ⅲ protein. Ycom1D3 bound specifically to both the soluble KDR-Ⅲ and the cell-surface expressed KDR. Ycom1D3 effectively blocked VEGF/KDR interaction and inhibited VEGF-stimulated KDR activation in human endothelial cells. Furthermore, the antibody efficiently neutralized VEGF-induced mitogenesis of human endothelial cells. CONCLUSION: Our results suggest that the anti-KDR mAb, Ycom1D3, has potential applications in the treatment of cancer and other diseases where pathological angiogenesis is involved.

  14. Role of TRPM7 channels in hyperglycemia-mediated injury of vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Huawei Sun

    Full Text Available This study investigated the change of transient receptor potential melastatin 7 (TRPM7 expression by high glucose and its role in hyperglycemia induced injury of vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs were incubated in the presence or absence of high concentrations of D-glucose (HG for 72 h. RT-PCR, Real-time PCR, Western blotting, Immunofluorescence staining and whole-cell patch-clamp recordings showed that TRPM7 mRNA, TRPM7 protein expression and TRPM7-like currents were increased in HUVECs following exposure to HG. In contrast to D-glucose, exposure of HUVECs to high concentrations of L-glucose had no effect. HG increased reactive oxygen species (ROS generation, cytotoxicity and decreased endothelial nitric oxide synthase protein expression, which could be attenuated by knockdown of TRPM7 with TRPM7 siRNA. The protective effect of silencing TRPM7 against HG induced endothelial injury was abolished by U0126, an inhibitor of the extracellular signal-regulated kinase signaling pathway. These observations suggest that TRPM7 channels play an important role in hyperglycemia-induced injury of vascular endothelial cells.

  15. Effects of the vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor SU5416 on in vitro cultures of Plasmodium falciparum

    DEFF Research Database (Denmark)

    Hempel, Casper; Hoyer, Nils; Staalsø, Trine;

    2014-01-01

    BACKGROUND: Vascular endothelial growth factor (VEGF) is taken up by parasitized red blood cells during malaria and stimulates intra-erythrocytic growth of Plasmodium falciparum in vitro. The cause and consequence of this uptake is not understood. METHODS: Plasmodium falciparum was cultured...... in vitro. Parasite growth and intracellular VEGF levels were assessed using flow cytometry. Intracellular VEGF was visualized by fluorescence immunocytochemistry. Phosphorylated tyrosine was measured by western blotting. In vivo assessment of intra-erythrocytic VEGF was performed in Plasmodium berghei ANKA...

  16. Tissue engineered pre-vascularized buccal mucosa equivalents utilizing a primary triculture of epithelial cells, endothelial cells and fibroblasts.

    Science.gov (United States)

    Heller, M; Frerick-Ochs, E V; Bauer, H-K; Schiegnitz, E; Flesch, D; Brieger, J; Stein, R; Al-Nawas, B; Brochhausen, C; Thüroff, J W; Unger, R E; Brenner, W

    2016-01-01

    Artificial generated buccal mucosa equivalents are a promising approach for the reconstruction of urethral defects. Limiting in this approach is a poor blood vessel supply after transplantation, resulting in increased morbidity and necrosis. We generated a pre-vascularized buccal mucosa equivalent in a tri-culture of primary buccal epithelial cells, fibroblasts and microvascular endothelial cells, using a native collagen membrane as a scaffold. A successful pre-vascularization and dense formation of capillary-like structures at superficial areas was demonstrated. The lumen size of pre-formed blood vessels corresponded to the capillary size in vivo (10-30 μm). Comparing native with a highly cross-linked collagen membrane we found a distinct higher formation of capillary-like structures on the native membrane, apparently caused by higher secretion of angiogenic factors such as PDGF, IL-8 and angiopoietin by the cells. These capillary-like structures became functional blood vessels through anastomosis with the host vasculature after implantation in nude mice. This in vitro method should result in an accelerated blood supply to the biomaterial with cells after transplantation and increase the succes rates of the implant material.

  17. INTERACTIONS BETWEEN THE HUMAN GASTRIC CARCINOMA CELL AND THE HUMAN VASCULAR ENDOTHELIAL CELL

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To definite the interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the establishment and maintenance of the tumor vascular system and the tumor hematogenous metastasis.Methods We prepared the conditioned mediums of each cell so as to study the effect of the conditioned medium on itself or others by MTT colorimetry. The comprehensive effect of interactions between two cells was determined by stratified transfilter co-culture or direct contact co-culture.Results The conditioned medium of human gastric carcinoma cell can stimulate the proliferation of the human vascular endothelial cell, but the CM of HVEC can inhibit the growth of HGCC. Both kinds of cells can inhibit the growth of itself. The ultimate comprehensive effect of the interactions between two kinds of cells was increase of total cell numbers.Conclusion There exist the complicated interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the tumor angiogenesis and the tumor hematogenous metastasis. The ultimate comprehensive effect of the interactions is increase of total cells numbers and tumor volume.

  18. Human endothelial stem/progenitor cells, angiogenic factors and vascular repair

    OpenAIRE

    Watt, Suzanne M.; Athanassopoulos, Athanasios; Harris, Adrian L.; Tsaknakis, Grigorios

    2010-01-01

    Neovascularization or new blood vessel formation is of utmost importance not only for tissue and organ development and for tissue repair and regeneration, but also for pathological processes, such as tumour development. Despite this, the endothelial lineage, its origin, and the regulation of endothelial development and function either intrinsically from stem cells or extrinsically by proangiogenic supporting cells and other elements within local and specific microenvironmental niches are stil...

  19. Gene Expression Analysis of Human Vascular Endothelial Cells Treated by Ouabain in Pathological Concentration

    Institute of Scientific and Technical Information of China (English)

    任延平; 吕卓人

    2004-01-01

    Objectives To study the gene expression of human vascular endothelial cells (HUVEC) treated by ouabain in pathological concentration. Methods The response of endothelial cells to ouabain of 1.8 nmol/L was explored with a complementary DNA microarray representing 8 464 different human genes. Results The results of mRNA profiles analysis indicated that 129 of the genes were differently expressed, 26 were upregulated. Conclusions The pathological role of ouabain on HUVEC may be involved in the controlling of DNA transcription、protein translation、 metabolism and signal transduction.

  20. Angiogenic Type I Collagen Extracellular Matrix Integrated with Recombinant Bacteriophages Displaying Vascular Endothelial Growth Factors.

    Science.gov (United States)

    Yoon, Junghyo; Korkmaz Zirpel, Nuriye; Park, Hyun-Ji; Han, Sewoon; Hwang, Kyung Hoon; Shin, Jisoo; Cho, Seung-Woo; Nam, Chang-Hoon; Chung, Seok

    2016-01-21

    Here, a growth-factor-integrated natural extracellular matrix of type I collagen is presented that induces angiogenesis. The developed matrix adapts type I collagen nanofibers integrated with synthetic colloidal particles of recombinant bacteriophages that display vascular endothelial growth factor (VEGF). The integration is achieved during or after gelation of the type I collagen and the matrix enables spatial delivery of VEGF into a desired region. Endothelial cells that contact the VEGF are found to invade into the matrix to form tube-like structures both in vitro and in vivo, proving the angiogenic potential of the matrix.

  1. The vascular endothelial growth factor expression and vascular regeneration in infarcted myocardium by skeletal muscle satellite cells

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Myocardial infarction results in tissue necrosis, leading to cell loss and ultimately to cardiac failure. Implantation of skeletal muscle satellite cells into the scar area may compensate for the cell loss and provides a new strategy for infarct therapy. Vascular endothelial growth factor (VEGF) is a promising reagent for inducing myocardial angiogenesis. Skeletal myoblast transplantation has been shown to improve cardiac function in chronic heart failure models by regenerating muscle. We hypothesized that VEGF expression and vascular regeneration increased in infarcted myocardium by skeletal muscle satellite cells, which can promote vascular producing and improve survival environment in infarcted myocardium.Methods The skeletal muscle satellite cells were implanted into the infarcted myocardium in a model through ligated left anterior artery in Louis Inbrad Strain rat. Specimens were got for identifying the expression of VEGF and the density of vascular by immunochemical method at two weeks after implantation. Results The proliferation and differentiation of the skeletal muscle satellite cell was very well. The expression of VEGF was higher in the implanted group (146.83±2.49) than that in the control group (134.26±6.84) (P<0.05). The vascular density in the implanted group (13.00±1.51) was also higher than that in the control (10.68±1.79) (P<0.05). Conclusion The implanted satellite cell could excrete growth factor that would induce angiogenesis and improve cell survival environment in infarcted myocardium.

  2. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Lipsic, Erik; van der Meer, Peter; van der Harst, Pirn; Oeseburg, Hisko; Sarvaas, Gideon J. Du Marchie; Koster, Johan; Voors, Adriaan A.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Schoemaker, Regien G.

    2007-01-01

    Aims Erythropoietin (EPO) improves cardiac function and induces neovascutarization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculatur

  3. Effect of Danshen injection on the vascular endothelial function and renal function in patients with pregnancy induced hypertension syndrome

    Institute of Scientific and Technical Information of China (English)

    Jun-Qing Zhang; Wei Gao

    2016-01-01

    Objective:To explore the effect of Danshen injection on the vascular endothelial function and renal function in patients with pregnancy induced hypertension syndrome (PIH). Methods:A total of 100 patients with PIH who were admitted in our hospital from May, 2015 to May, 2016 were included in the study and randomized into the observation group and the control group. The patients in the control group were given blood pressure reduction, diuresis, spasmolysis, sedation, magnesium sulfate, and comprehensive nursing intervention. On this basis, the patients in the observation group were given additional Danshen injection (20 mL) + 5% glucose (250 mL), ivdrip, 1 time/d. After 10 d treatment, the efficacy was evaluated. The peripheral venous blood before and after treatment in the two groups was collected. The radioimmunoassay was used to detect ET-1. ELISA was used to detect Hcy. The immunoturbidimetry was used to detect vWF. The radioimmunoassay was used to detect BUN, Scr, UA, andβ2-MG. The standard sphygmomanometer was used to monitor the blood pressure and MAP was calculated. The biuret colorimetry was used to determine 24 h Upro. Results:The reduced degree of ET-1, Hcy, and vWF after treatment in the observation group was significantly superior to that in the control group. The reduced degree of BUN, Scr, UA, andβ2-MG after treatment in the observation group was significantly superior to that in the control group. The reduced degree of MPA and 24 h Upro after treatment in the observation group was significantly superior to that in the control group.Conclusions:Routine treatments, comprehensive nursing intervention, and Danshen injection in the treatment of PIH can effectively improve the vascular endothelial function and renal function in order to reduce the blood pressure and alleviate the urine protein.

  4. Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells.

    Science.gov (United States)

    Abbasian, Nima; Burton, James O; Herbert, Karl E; Tregunna, Barbara-Emily; Brown, Jeremy R; Ghaderi-Najafabadi, Maryam; Brunskill, Nigel J; Goodall, Alison H; Bevington, Alan

    2015-09-01

    Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.

  5. Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome.

    Science.gov (United States)

    Marchesi, Chiara; Ebrahimian, Talin; Angulo, Orlando; Paradis, Pierre; Schiffrin, Ernesto L

    2009-12-01

    The metabolic syndrome represents a constellation of cardiovascular risk factors that promote the development of cardiovascular disease. Oxidative stress is a mediator of endothelial dysfunction and vascular remodeling. We investigated vascular dysfunction in the metabolic syndrome and the oxidant mechanisms involved. New Zealand obese (NZO) mice with metabolic syndrome and New Zealand black control mice were studied. NZO mice showed insulin resistance and increased visceral fat and blood pressure compared with New Zealand black mice. Mesenteric resistance arteries from NZO mice exhibited increased media:lumen ratio and media cross-sectional area, demonstrating hypertrophic vascular remodeling. Endothelium-dependent relaxation to acetylcholine, assessed by pressurized myography, was impaired in NZO mice, not affected by N(G)-nitro-l-arginine methyl ester, inhibitor of endothelial NO synthase, and improved by the antioxidant Tempol, suggesting reduced NO bioavailability and increased oxidative stress. Dimer:monomer ratio of endothelial NO synthase was decreased in NZO mice compared with New Zealand black mice, suggesting endothelial NO synthase uncoupling. Furthermore, vascular superoxide and peroxynitrite production was increased, as well as adhesion molecule expression. Perivascular adipose tissue of NZO mice showed increased superoxide production and NADPH oxidase activity, as well as adipocyte hypertrophy, associated with inflammatory Mac-3-positive cell infiltration. Vasoconstriction to norepinephrine decreased in the presence of perivascular adipose tissue in New Zealand black mice but was unaffected by perivascular adipose tissue in NZO mice, suggesting loss of perivascular adipose tissue anticontractile properties. Our data suggest that this rodent model of metabolic syndrome is associated with perivascular adipose inflammation and oxidative stress, hypertrophic resistance artery remodeling, and endothelial dysfunction, the latter a result of decreased NO

  6. Improved hemocompatibility and endothelialization of vascular grafts by covalent immobilization of sulfated silk fibroin on poly(lactic-co-glycolic acid) scaffolds.

    Science.gov (United States)

    Liu, Haifeng; Li, Xiaoming; Niu, Xufeng; Zhou, Gang; Li, Ping; Fan, Yubo

    2011-08-08

    Endothelialization of vascular grafts prior to implantation has been investigated widely to enhance biocompatibility and antithrombogenicity. Thrombosis of artificial vessels is typically caused by platelet adhesion and agglomeration following endothelial cells detachment when exposed to the shear stress of blood circulation. The present study thus aimed at preventing platelet adhesion and aggregation onto biomaterials before the endothelial confluence is fully achieved. We report this modification of poly(lactic-co-glycolic acid) (PLGA) scaffolds, both to impart hemocompatibility to prevent platelet adhesion and aggregation before the endothelial confluence is fully achieved and to support EC growth to accelerate endothelialization. The modification was achieved by covalent immobilization of sulfated silk fibroin on PLGA scaffolds using γ irradiation. Using phosphate-buffered saline (PBS) as an aging medium, it was demonstrated that the scaffolds prepared by γ irradiation had a good retention of sulfated silk fibroin. The systematic in vitro hemocompatibility evaluation revealed that sulfated silk fibroin covalently immobilized PLGA (S-PLGA) scaffolds-reduced platelet adhesion and activation, prolonged whole blood clotting time, activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). To evaluate further in vitro cytocompatibility of the scaffolds, we seeded vascular ECs on the scaffolds and cultured them for 2 weeks. The ECs were seen to attach and proliferate well on S-PLGA scaffolds, forming cell aggregates that gradually increased in size and fused with adjacent cell aggregates to form a monolayer covering the scaffold surface. Moreover, it was demonstrated through the gene transcript levels and the protein expressions of EC-specific markers that the cell functions of ECs on S-PLGA scaffolds were better preserved than those on PLGA scaffolds. Therefore, this study has described the generation of a vascular graft that

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The success of gene therapy depends largely on the efficacy of gene delivery vector systems that can deliver genes to target organs or cells selectively and efficiently with minimal toxicity. Here, we show that by using the HRE.ppET-1 regulatory element, we were able to restrict expression of the transgene of vascular endothelial growth factor (VEGF) to endothelial cells exclusively in hypoxic conditions. Eukaryotic expression vectors such as pEGFP-HRE.ppET-1, pcDNA3.1-VEGF+Pa, pcDNA3.1-ppET-1+ EGF+Pa, and pcDNA3.1-HRE.ppET-1+VEGF+Pa were constructed by using a series of nuclear molecule handling methods like PCR, enzyme digestion. The recombinant vectors were transfected into HUVEC cells and HL7702 cells by the lipofectin method. GFP expression was observed with a fluorescence microscope to validate the specificity of expression in endothelial cells under the regulation of HRE.ppET-1 element. Cobalt chloride (final concentration 100 μmol/L) was added to the medium to mimic hypoxia in vitro. After transfection of vectors, the expression of VEGF mRNA was detected by RT-PCR, and the expression of VEGF was detected by Western blotting and ELISA methods under normoxia and hypoxia, respectively. The cell proliferation rate was detected by the MTT test. The ex- pression of GFP revealed that the exterior gene was transcripted effectively in endothelial cells regu- lated by the HRE.ppET-1 element, while the expression of GFP was very weak in nonendothelial cells. The results of RT-PCR, Western blotting and ELISA showed that VEGF gene expression in the pcDNA3.1-HRE.ppET-1+VEGF+Pa group and in the pcDNA3.1-ppET-1+VEGF+Pa group was higher in hypoxia than it was in normoxia (P<0.05). The MTT test showed that the proliferation rate of HUVEC transfected with HPVA under hypoxia exceeded that of the control group. We conclude that the HRE.ppET-1 element was expressed specifically in endothelial cells, and can increase the expression of VEGF in hypoxia and stimulate proliferation

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  9. Electrostatic endothelial cell seeding technique for small-diameter (<6 mm) vascular prostheses: feasibility testing.

    Science.gov (United States)

    Bowlin, G L; Rittgers, S E

    1997-01-01

    Multiple studies have indicated the importance of surface charge in the adhesion of multiple cardiovascular cell lines including platelets and endothelial cells on the substrate materials (1,4,7-10,12-15). It is the purpose of this article to report a feasibility study conducted using an electrostatic endothelial cell seeding technique. The feasibility study was conducted using human umbilical vein endothelial cells (HUVEC), a static pool apparatus, a voltage source, and a parallel plate capacitor. The HUVEC concentration and seeding times were constant at 560,000 HUVEC/ml and 30 min, respectively. Scanning electron microscopy examination of the endothelial cell adhesion indicated that an induced temporary positive surface charge on e-PTFE graft material enhances the number and the maturation (flattening) of HUVECs adhered. The results indicated that the total number of endothelial cells adhered (70.9 mm2) was increased from 9198 +/- 1194 HUVECs on the control (no induced surface charge) e-PTFE to 22,482 +/- 4814 HUVECs (2.4 x control) on the maximum induced positive surface charge. The total number of cells in the flattened phase of adhesion increased from 837 +/- 275 to 6785 +/- 1012 HUVECs (8.1x) under identical conditions. Thus, the results of the feasibility study support the premise that electrostatic interaction is an important factor in both the endothelial cell adhesion and spreading processes and suggest that the electrostatic seeding technique may lead to an increased patency of small diameter (<6 mm) vascular prostheses.

  10. The relationship between serum vascular endothelial growth factor A and microsatellite instability in colorectal cancer

    DEFF Research Database (Denmark)

    Hansen, T F; Jensen, L H; Spindler, K-L G;

    2011-01-01

    AIM: It has been suggested that colorectal neoplasms with or without microsatellite instability (MSI) can stimulate angiogenesis in different ways. The vascular endothelial growth factor (VEGF) system is essential for the angiogenetic process and the growth of malignant tumours. The aim of this s......AIM: It has been suggested that colorectal neoplasms with or without microsatellite instability (MSI) can stimulate angiogenesis in different ways. The vascular endothelial growth factor (VEGF) system is essential for the angiogenetic process and the growth of malignant tumours. The aim...... lacking protein expression of any of the four mismatch repair genes (MLH1, PMS2, MSH2 or MSH6) were labelled as high MSI. The rest were considered to be microsatellite stable (MSS). The serum VEGF-A analyses were performed by ELISA. RESULTS: The tumours of 15 patients in the test cohort and 27...

  11. A novel adipocytokine, chemerin exerts anti-inflammatory roles in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamawaki, Hideyuki, E-mail: yamawaki@vmas.kitasato-u.ac.jp [Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori 034-8628 (Japan); Kameshima, Satoshi; Usui, Tatsuya; Okada, Muneyoshi; Hara, Yukio [Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori 034-8628 (Japan)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer Chemerin is a novel adipocytokine with almost unknown function in vasculature. Black-Right-Pointing-Pointer Chemerin activates Akt/eNOS/NO pathways in endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-{alpha}-induced monocyte adhesion to endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-induced VCAM-1 via suppressing NF-{kappa}B and p38 signal. Black-Right-Pointing-Pointer Chemerin is anti-inflammatory through producing NO in vascular endothelium. -- Abstract: Chemerin is a recently identified adipocytokine which plays a role on inflammation and adipocytes metabolism. However, its function in vasculature is largely unknown. We examined the effects of chemerin on vascular endothelial inflammatory states. Treatment of human umbilical vein endothelial cells with chemerin (300 ng/ml, 20 min) induced phosphorylation of Akt (Ser473) and endothelial nitric oxide (NO) synthase (eNOS) (Ser1177). Consistently, chemerin increased intracellular cyclic GMP content. Pretreatment with chemerin (1-300 ng/ml, 24 h) significantly inhibited phosphorylation of nuclear factor (NF)-{kappa}B p65 (Ser536) and p38 as well as vascular cell adhesion molecule (VCAM)-1 expression induced by tumor necrosis factor (TNF)-{alpha} (5 ng/ml, 20 min-6 h). Inhibitor of NF-{kappa}B or p38 significantly inhibited the TNF-{alpha}-induced VCAM-1 expression. Chemerin also inhibited TNF-{alpha}-induced VCAM-1 expression in rat isolated aorta. Moreover, chemerin significantly inhibited monocytes adhesion to TNF-{alpha}-stimulated endothelial cells. The inhibitory effect of chemerin on TNF-{alpha}-induced VCAM-1 was reversed by a NOS inhibitor. Conversely, an NO donor, sodium nitroprusside significantly inhibited TNF-{alpha}-induced VCAM-1. The present results for the first time demonstrate that chemerin plays anti-inflammatory roles by preventing TNF-{alpha}-induced VCAM-1 expression and monocytes adhesion in vascular

  12. Construction and analysis of SSH cDNA library of human vascular endothelial cells related to gastrocarcinoma

    OpenAIRE

    2003-01-01

    AIM: To construct subtracted cDNA libraries of human vascular endothelial cells (VECs) related to gastrocarcinoma using suppression substractive hybridization (SSH) and to analyze cDNA libraries of gastrocarcinoma and VECs in Cancer Gene Anatomy Project (CGAP) database.

  13. Pretreatment with recombinant human vascular endothelial growth factor virus replication and inflammation in a perinatal lamb model of RSV infection

    Science.gov (United States)

    Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. Innate immune components including surfactant proteins A and D, and beta defensins have putative antimicrobial activity against pulmonary pathogens inc...

  14. The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells.

    Science.gov (United States)

    Mukovozov, Ilya; Huang, Yi-Wei; Zhang, Qiuwang; Liu, Guang Ying; Siu, Allan; Sokolskyy, Yaroslav; Patel, Sajedabanu; Hyduk, Sharon J; Kutryk, Michael J B; Cybulsky, Myron I; Robinson, Lisa A

    2015-10-01

    The secreted neurorepellent Slit2, acting through its transmembrane receptor, Roundabout (Robo)-1, inhibits chemotaxis of varied cell types, including leukocytes, endothelial cells, and vascular smooth muscle cells, toward diverse attractants. The role of Slit2 in regulating the steps involved in recruitment of monocytes in vascular inflammation is not well understood. In this study, we showed that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, as well as to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of constitutively active plasmids revealed that Slit2 inhibited postadhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. We further found that Slit2 inhibited chemotaxis of monocytes toward CXCL12 and CCL2. To determine whether Slit2 and Robo-1 modulate pathologic monocyte recruitment associated with vascular inflammation and cardiovascular disease, we tested PBMC from patients with coronary artery disease. PBMC from these patients had reduced surface levels of Robo-1 compared with healthy age- and sex-matched subjects, and Slit2 failed to inhibit chemotaxis of PBMC of affected patients, but not healthy control subjects, toward CCL2. Furthermore, administration of Slit2 to atherosclerosis-prone LDL receptor-deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. These results demonstrate that Slit2 inhibits chemotaxis of monocytes, as well as their ability to stabilize adhesions and resist detachment forces. Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation and atherosclerosis.

  15. Platelet and endothelial adhesion on fluorosurfactant polymers designed for vascular graft modification

    OpenAIRE

    Tang, Chad; Kligman, Faina; Larsen, Coby C.; KOTTKE-MARCHANT, KANDICE; Marchant, Roger E.

    2009-01-01

    A prominent failure mechanism of small-diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts is platelet-mediated thrombosis. We have designed surface modification for ePTFE consisting of a self-assembling fluorosurfactant polymer (FSP) bearing biologically active ligands, including adhesive peptides and polysaccharide moieties. The goal of this biomimetic construct is to improve graft hemocompatibility by promoting rapid surface endothelialization, while minimizing platelet adhes...

  16. Human Vascular Endothelial Growth Factor cDNA Cloning and Expression in Osteoblasts

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Human vascular endothelial growth factor (VEGF) cDNA was amplified by nested polymerase chain reaction method from the HL60 cells. Then a pCD-hVEGF165 recombinant plasmid was constructed. Rabbit osteoblasts were transfected with pCD-hVEGF165 plasmid by lipofectin mediated gene transfer. The transient expressive results were detected by immunohistochemical method. It was observed that the expression of human VEGF gene was detected 72 h after transfecting distinctly.

  17. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells.

    Science.gov (United States)

    Berrich, Moez; Kieda, Claudine; Grillon, Catherine; Monteil, Martine; Lamerant, Nathalie; Gavard, Julie; Boulouis, Henri Jean; Haddad, Nadia

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of any available feline endothelial cell lines.To this purpose, we have developed nine feline EC lines which allowed comparing the effects of Bartonella strains on human and feline micro-vascular ECs representative of the infection development sites such as skin, versus macro-vascular ECs, such as umbilical vein.Our model revealed intrinsic differences between human (Human Skin Microvascular ECs -HSkMEC and Human Umbilical Vein ECs - iHUVEC) and feline ECs susceptibility to Bartonella henselae infection.While no effect was observed on the feline ECs upon Bartonella henselae infection, the human ones displayed accelerated angiogenesis and wound healing.Noticeable differences were demonstrated between human micro- and macro-vasculature derived ECs both in terms of pseudo-tube formation and healing. Interestingly, Bartonella henselae effects on human ECs were also elicited by soluble factors.Neither Bartonella henselae-infected Human Skin Microvascular ECs clinically involved in bacillary angiomatosis, nor feline ECs increased cAMP production, as opposed to HUVEC.Bartonella henselae could stimulate the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) in homologous cellular systems and trigger VEGF production by HSkMECs only, but not iHUVEC or any feline ECs tested.These results may explain the decreased pathogenic potential of Bartonella henselae infection for cats as compared to humans and strongly suggest that an autocrine secretion of VEGF by human skin

  18. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells

    OpenAIRE

    Berrich, Moez; Kieda, Claudine; Grillon, Catherine; Monteil, Martine; Lamerant, Nathalie; Gavard, Julie; Haddad, Nadia

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of ...

  19. Differential Effects of Bartonella henselae on Human and Feline Macro- and Micro-Vascular Endothelial Cells

    OpenAIRE

    Moez Berrich; Claudine Kieda; Catherine Grillon; Martine Monteil; Nathalie Lamerant; Julie Gavard; Henri Jean Boulouis; Nadia Haddad

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of any...

  20. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Moez Berrich

    Full Text Available Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs, namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host ECs vs feline (reservoir host ECs has been carried out because of the absence of any available feline endothelial cell lines.To this purpose, we have developed nine feline EC lines which allowed comparing the effects of Bartonella strains on human and feline micro-vascular ECs representative of the infection development sites such as skin, versus macro-vascular ECs, such as umbilical vein.Our model revealed intrinsic differences between human (Human Skin Microvascular ECs -HSkMEC and Human Umbilical Vein ECs - iHUVEC and feline ECs susceptibility to Bartonella henselae infection.While no effect was observed on the feline ECs upon Bartonella henselae infection, the human ones displayed accelerated angiogenesis and wound healing.Noticeable differences were demonstrated between human micro- and macro-vasculature derived ECs both in terms of pseudo-tube formation and healing. Interestingly, Bartonella henselae effects on human ECs were also elicited by soluble factors.Neither Bartonella henselae-infected Human Skin Microvascular ECs clinically involved in bacillary angiomatosis, nor feline ECs increased cAMP production, as opposed to HUVEC.Bartonella henselae could stimulate the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2 in homologous cellular systems and trigger VEGF production by HSkMECs only, but not iHUVEC or any feline ECs tested.These results may explain the decreased pathogenic potential of Bartonella henselae infection for cats as compared to humans and strongly suggest that an autocrine secretion of VEGF by human

  1. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway

    OpenAIRE

    Paré-Brunet, Laia; Glubb, Dylan; Evans, Patrick; Berenguer-Llergo, Antoni; Etheridge, Amy S.; Skol, Andrew D.; Di Rienzo, Anna; Duan, Shiwei; Gamazon, Eric R.; Innocenti, Federico

    2013-01-01

    Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU a...

  2. Proliferation of endothelial cells on the plasma-treated segmented-polyurethane surface: attempt of construction of a small caliber hybrid vascular graft and antithrombogenicity.

    Science.gov (United States)

    Kaibara; Takahashi; Kurotobi; Suzuki

    2000-12-30

    To prepare a porous segmented-polyurethane (SPU) tube, a solution of SPU containing different concentrations of NaCl was coated on a glass rod and the coated SPU was immediately immersed in water. When the surface of the porous SPU, where bovine aortic endothelial cells are not normally capable of adhering and proliferating, was modified by plasma treatment, the proliferation of endothelial cells could be drastically improved. The cells proliferated confluently on the porous SPU surface prepared at low concentrations of NaCl below 10 g per 100 ml, but poorly on the porous surface prepared at high concentrations of NaCl. The construction of a hybrid vascular graft consisting of a porous SPU tube (2 mm in inner diameter, 5 cm in length) and endothelial cells was attempted. The cells cultured on the inner surface of the tube proliferated to confluency everywhere. From an in vitro antithrombogenic evaluation test, which involved the use of human blood, the present hybrid graft can be considered to provide an inert surface against thrombus formation and blood coagulation. Negligible changes in shape of human leukocytes in contact with bovine aortic endothelial cell surface occurred, suggesting that the bovine aortic endothelial cells used are immunologically less active against human blood.

  3. Impact of simulated microgravity on the secretory and adhesive activity of cultured human vascular endothelial cells.

    Science.gov (United States)

    Rudimov, Evgeny; Buravkova, Ludmila; Pogodina, Margarita; Andrianova, Irina

    The layer of vascular endothelial cells (ECs) is a dynamic,disseminated organ that perform the function of an interface between the blood and vascular wall. The endothelial monolayer is able to quickly respond to changes in the microenvironment due to its synthesis of vasoactive substances, chemokines, adhesion molecules expression, etc. ECs are highly sensitive to gravitational changes and capable of short-term and long-term responses (Sangha et al., 2001; Buravkova et al., 2005; Infanger et al., 2006, 2007. However, the question remains how to reflect the impact of microgravity on endothelium under the inflammatory process. Therefore, the aim of this study was to investigate secretory and adhesive activity of human umbilical vein endothelial cells (HUVECs) during simulated microgravity and TNF-a activation. HUVECs were isolated according to Gimbrone et al. (1978) in modification A. Antonov (1981) and used for experiments at 2-4 passages. HUVECs were activated by low level of TNF-a (2 ng/ml). Microgravity was generated by Random Positioning Machine (RPM, Dutch Space, Leiden) placed into the thermostat at 37°C. After 24 hours of clinorotation we measured adhesion molecules expression on the cell surface (ICAM-1, VCAM-1, PECAM-1, E-selectin, CD144, endoglin (CD105)) and cell viability using a flow cytometry. To evaluate the level of target gene expression was used the real time RT-PCR. IL-6 and IL-8 concentration was measured in the conditioned medium of HUVECs by using the ELISA test. We found that simulated microgravity within 24 hours caused a decrease of ICAM-1, CD144, and E-selectin expression, at the same time not affect the cell viability, endoglin and PECAM-1 expression on the surface HUVEC. Furthermore, there were no changes of the level of IL-6 and IL-8 gene expression and their products in the culture medium. TNF-activated HUVECs showed an increase in gene expression of interleukins and molecules involved in the adhesion process, which also was confirmed

  4. Strategies and techniques to enhance the in situ endothelialization of small-diameter biodegradable polymeric vascular grafts.

    Science.gov (United States)

    Melchiorri, Anthony J; Hibino, Narutoshi; Fisher, John P

    2013-08-01

    Due to the lack of success in small-diameter (strategies have evolved utilizing a tissue-engineering approach. Much of this work has focused on enhancing the endothelialization of these grafts. A healthy, confluent endothelial layer provides dynamic control over homeo-stasis, influencing and preventing thrombosis and smooth muscle cell proliferation that can lead to intimal hyperplasia. Strategies to improve endothelialization of biodegradable polymeric grafts have encompassed both chemical and physical modifications to graft surfaces, many focusing on the recruitment of endothelial and endothelial progenitor cells. This review aims to provide a compilation of current and developing strategies that utilize in situ endothelialization to improve vascular graft outcomes, providing a context for the future directions of vascular tissue-engineering strategies that do not require preprocedural cell seeding.

  5. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.

    Science.gov (United States)

    Donato, Anthony J; Magerko, Katherine A; Lawson, Brooke R; Durrant, Jessica R; Lesniewski, Lisa A; Seals, Douglas R

    2011-09-15

    We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5-7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with l-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P SIRT-1 protein expression (r = 0.44, P SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing.

  6. PCB 77 dechlorination products modulate pro-inflammatory events in vascular endothelial cells.

    Science.gov (United States)

    Eske, Katryn; Newsome, Bradley; Han, Sung Gu; Murphy, Margaret; Bhattacharyya, Dibakar; Hennig, Bernhard

    2014-05-01

    Persistent organic pollutants such as polychlorinated biphenyls (PCBs) are associated with detrimental health outcomes including cardiovascular diseases. Remediation of these compounds is a critical component of environmental policy. Although remediation efforts aim to completely remove toxicants, little is known about the effects of potential remediation byproducts. We previously published that Fe/Pd nanoparticles effectively dechlorinate PCB 77 to biphenyl, thus eliminating PCB-induced endothelial dysfunction using primary vascular endothelial cells. Herein, we analyzed the toxic effects of PCB congener mixtures (representative mixtures of commercial PCBs based on previous dechlorination data) produced at multiple time points during the dechlorination of PCB 77 to biphenyl. Compared with pure PCB 77, exposing endothelial cells to lower chlorinated PCB byproducts led to improved cellular viability, decreased superoxide production, and decreased nuclear factor kappa B activation based on duration of remediation. Presence of the parent compound, PCB 77, led to significant increases in mRNA and protein inflammatory marker expression. These data implicate that PCB dechlorination reduces biological toxicity to vascular endothelial cells.

  7. Effect of Shengmai Injection on Vascular Endothelial and Heart Functions in Patients with Coronary Heart Disease Complicated with Diabetes Mellitus

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ya-chen; LU Bao-jing; ZHAO Mei-hua; RONG Ye-zhi; CHEN Rui-ming

    2008-01-01

    Objective: To study the effect of Shengrnai injection (生脉注射液, SMI) on vascular endothelial and heart functions in coronary heart disease patients complicated with diabetes mellitus (CHD-DM). Methods: One hundred and twenty patients with CHD-DM, their diagnosis confirmed by coronary arteriography, were equally randomized into a control group treated with conventional treatment and a treated group treated with conventional treatment plus SMI. The changes in blood levels of nitric oxide (NO), endothelin-1 (ET-1) and angiotensin Ⅱ (Ang Ⅱ ), as well as endothelium-dependent vascular dilating function and heart function in the patients were observed before treatment and after the 3-week treatment. Results: After being treated with SMI for 3 weeks, in the treated group, blood level of NO was raised significantly from 69.8 ± 33.1 μ mol/L to 120.1 ± 50.8 μ mol/L, and ET-1 was lowered from 70.1 ± 32.1 ng/L to 46.2±21.3 ng/L, respectively (P<0.01); that of Ang Ⅱ was lowered from 81.3 ± 24.3 ng/L to 50.2 ± 27.3 ng/L (P<0.01); brachial arterial post-congestion blood flow increasing rate was raised from 389.4 ± 26.3% to 459.3 ± 27.8% (P<0.01); and the improvement in heart function as seen through the ejection fraction (EF) was increased from 44 ± 5% to 68 ± 6% (P<0.01), all the changes being more significant than those in the control group (all P<0.01). Conclusion: SMI can improve not only the endothelial function in CHD-DM patients, but also heart contraction significantly.

  8. Characterization of ionizing radiation-induced unfolded protein response in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ju; Lee, Yoon Jin; Kang, Seong Man [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-04-15

    Misfolded or unfolded proteins within the endoplasmic reticulum (ER stress), viral infection, or amino acid deprivation induce eukaryotic translation initiation factor 2α phosphorylation (eIF2α) in eukaryotic cells, repressing global protein synthesis coincident with preferential translation of activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of genes involved in amino acid metabolism, cellular redox homeostasis, and regulation of apoptosis. When the eIF2α/ATF4 pathway is initiated by ER stress, the pathway is referred toas the unfolded protein response (UPR). In addition to DNA, proteins may be initial and important targets of ionizing radiation (IR), and the damaged protein can trigger ER stress pathway. Recent investigations suggested that IR induces ER stress followed by UPR in various cell types including intestinal epithelial cells. We conducted this study to determine whether IR can activate UPR in human vascular endothelial cells. Our data have shown that IR increased PERK-dependent eIF2α phosphorylation accompanied by induction in ATF4 protein levels in human vascular endothelial cells without alterations in expressions of XBP-1s and GRP78. Based on these data, we suggest that IR selectively activates PERK branch of unfolded protein response in human vascular endothelial cells.

  9. [Influence of n-hexane on vascular endothelial active substances in brain tissue in mice].

    Science.gov (United States)

    Lin, L; Zhang, Z Q; Zhang, C Z

    2017-01-20

    Objective: To investigate the influence of n-hexane on vascular endothelial active substances in brain tissue in mice and its significance. Methods: A total of 48 healthy Kunming mice were randomly divided into high-dose exposure group, middle-dose exposure group, low-dose exposure group, and control group, with 12 mice in each group. All groups except the control group were exposed to n-hexane via static inhalation (0.035 g/L, 0.018 g/L, and 0.009 g/L for the high-, middle-, and low-dose exposure groups, respectively) 4 hours a day for 21 days. the mice in the control groups were not exposed to n-hexane. After the exposure, the lev-els of endothelin-1 (ET-1) , nitric oxide (NO) , and angiotensin II (Ang II) in brain tissue were measured in all groups. Results: There were significant differences in the levels of ET-1, NO, and Ang II between the three ex-posure groups and the control group (PHexane can affect the vascular endothe-lial active substances in brain tissue in mice, and the changes and imbalance in vascular endothelial active sub-stances may be one of the reasons for central nervous system impairment caused by n-hexane.

  10. Vascular Response to Graded Angiotensin II Infusion in Offspring Subjected to High-Salt Drinking Water during Pregnancy: The Effect of Blood Pressure, Heart Rate, Urine Output, Endothelial Permeability, and Gender.

    Science.gov (United States)

    Pezeshki, Zahra; Eshraghi-Jazi, Fatemeh; Nematbakhsh, Mehdi

    2014-01-01

    Introduction. Rennin-angiotensin system and salt diet play important roles in blood pressure control. We hypothesized that the high-salt intake during pregnancy influences the degree of angiotensin-dependent control of the blood pressure in adult offspring. Methods. Female Wistar rats in two groups (A and B) were subjected to drink tap and salt water, respectively, during pregnancy. The offspring were divided into four groups as male and female offspring from group A (groups 1 and 2) and from group B (groups 3 and 4). In anesthetized matured offspring mean arterial pressure (MAP), heart rate and urine output were measured in response to angiotensin II (AngII) (0-1000 ng/kg/min, iv) infusion. Results. An increase in MAP was detected in mothers with salt drinking water (P < 0.05). The body weight increased and kidney weight decreased significantly in male offspring from group 3 in comparison to group 1 (P < 0.05). MAP and urine volume in response to AngII infusion increased in group 3 (P < 0.05). These findings were not observed in female rats. Conclusion. Salt overloading during pregnancy had long-term effects on kidney weight and increased sex-dependent response to AngII infusion in offspring (adult) that may reveal the important role of diet during pregnancy in AngII receptors.

  11. Vascular Response to Graded Angiotensin II Infusion in Offspring Subjected to High-Salt Drinking Water during Pregnancy: The Effect of Blood Pressure, Heart Rate, Urine Output, Endothelial Permeability, and Gender

    Directory of Open Access Journals (Sweden)

    Zahra Pezeshki

    2014-01-01

    Full Text Available Introduction. Rennin-angiotensin system and salt diet play important roles in blood pressure control. We hypothesized that the high-salt intake during pregnancy influences the degree of angiotensin-dependent control of the blood pressure in adult offspring. Methods. Female Wistar rats in two groups (A and B were subjected to drink tap and salt water, respectively, during pregnancy. The offspring were divided into four groups as male and female offspring from group A (groups 1 and 2 and from group B (groups 3 and 4. In anesthetized matured offspring mean arterial pressure (MAP, heart rate and urine output were measured in response to angiotensin II (AngII (0-1000 ng/kg/min, iv infusion. Results. An increase in MAP was detected in mothers with salt drinking water (P<0.05. The body weight increased and kidney weight decreased significantly in male offspring from group 3 in comparison to group 1 (P<0.05. MAP and urine volume in response to AngII infusion increased in group 3 (P<0.05. These findings were not observed in female rats. Conclusion. Salt overloading during pregnancy had long-term effects on kidney weight and increased sex-dependent response to AngII infusion in offspring (adult that may reveal the important role of diet during pregnancy in AngII receptors.

  12. Potential benefits of exercise on blood pressure and vascular function.

    Science.gov (United States)

    Pal, Sebely; Radavelli-Bagatini, Simone; Ho, Suleen

    2013-01-01

    Physical activity seems to enhance cardiovascular fitness during the course of the lifecycle, improve blood pressure, and is associated with decreased prevalence of hypertension and coronary heart disease. It may also delay or prevent age-related increases in arterial stiffness. It is unclear if specific exercise types (aerobic, resistance, or combination) have a better effect on blood pressure and vascular function. This review was written based on previous original articles, systematic reviews, and meta-analyses indexed on PubMed from years 1975 to 2012 to identify studies on different types of exercise and the associations or effects on blood pressure and vascular function. In summary, aerobic exercise (30 to 40 minutes of training at 60% to 85% of predicted maximal heart rate, most days of the week) appears to significantly improve blood pressure and reduce augmentation index. Resistance training (three to four sets of eight to 12 repetitions at 10 repetition maximum, 3 days a week) appears to significantly improve blood pressure, whereas combination exercise training (15 minutes of aerobic and 15 minutes of resistance, 5 days a week) is beneficial to vascular function, but at a lower scale. Aerobic exercise seems to better benefit blood pressure and vascular function.

  13. Fenofibrate attenuates nicotine-induced vascular endothelial dysfunction in the rat.

    Science.gov (United States)

    Chakkarwar, Vishal Arvind

    2011-01-01

    The study has been designed to investigate the effect of fenofibrate on nicotine-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) was administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy of thoracic aorta. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase-polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration (TBARS) and aortic superoxide anion concentration were estimated to assess oxidative stress. Moreover, the serum lipid profile was assessed by estimating serum cholesterol, triglycerides and high density lipoprotein. The administration of nicotine induces VED by increased oxidative stress, altered lipid profile and impaired the integrity of vascular endothelium as assessed in terms of decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine produced oxidative stress, assessed in terms of increase in serum TBARS and aortic superoxide anion generation and increase in expression of mRNA for p22phox. Nicotine altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. However, treatment with fenofibrate (32 mg/kg, p.o.) markedly prevented nicotine-induced VED by decreasing oxidative stress and improving integrity of vascular endothelium, normalising the altered lipid profile, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic

  14. Contribution of blood platelets to vascular pathology in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Zhang W

    2013-11-01

    Full Text Available Wei Zhang,1,2 Wei Huang,1 Fang Jing11Department of Pharmacology, Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China; 2Shanghai Engineering Research Center of Molecular Therapy and Pharmaceutical Innovation, Shanghai, People's Republic of ChinaAbstract: Cerebral amyloid angiopathy (CAA is a critical factor in the pathogenesis of Alzheimer's disease (AD. In the clinical setting, nearly 98% AD patients have CAA, and 75% of these patients are rated as severe CAA. It is characterized by the deposition of the β-amyloid peptide (mainly Aβ40 in the walls of cerebral vessels, which induces the degeneration of vessel wall components, reduces cerebral blood flow, and aggravates cognitive decline. Platelets are anuclear cell fragments from bone marrow megakaryocytes and their function in hemostasis and thrombosis has long been recognized. Recently, increasing evidence suggests that platelet activation can also mediate the onset and development of CAA. First, platelet activation and adhesion to a vessel wall is the initial step of vascular injury. Activated platelets contribute to more than 90% circulating Aß (mainly Aβ1-40, which in turn activates platelets and results in the vicious cycle of Aβ overproduction in damaged vessel. Second, the uncontrolled activation of platelets leads to a chronic inflammatory reaction by secretion of chemokines (eg, platelet factor 4 [PF4], regulated upon activation normal T-cell expressed and presumably secreted [RANTES], and macrophage inflammatory protein [MIP-1α], interleukins (IL-1 β, IL-7, and IL-8, prostaglandins, and CD40 ligand (CD40L. The interaction of these biological response modulators with platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that contributes to CAA formation. Finally, activated platelets are the upholder of fibrin clots, which are structurally abnormal and resistant to degradation

  15. Functional characteristics of coronary vasomotor function following intramyocardial gene therapy with naked DNA encoding for vascular endothelial growth factor 165

    NARCIS (Netherlands)

    Tio, RA; Wijpkema, JS; Tan, ES; Asselbergs, FW; Hospers, GAP; Jessurun, GAJ; Zijlstra, F

    2005-01-01

    Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. VEGF gene therapy improves perfusion of ischemic myocardium in experimental models and possibly in patients with end-stage coronary artery disease. In addition to its proliferative and migratory effect on endothelial cells, it

  16. Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion

    Science.gov (United States)

    Ubezio, Benedetta; Blanco, Raquel Agudo; Geudens, Ilse; Stanchi, Fabio; Mathivet, Thomas; Jones, Martin L; Ragab, Anan; Bentley, Katie; Gerhardt, Holger

    2016-01-01

    Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning. DOI: http://dx.doi.org/10.7554/eLife.12167.001 PMID:27074663

  17. Protective effect and mechanism of vascular endothelial growth factor in vascular endothelial cell injury%VEGF对血管内皮细胞损伤的拮抗作用及作用机制

    Institute of Scientific and Technical Information of China (English)

    夏裕银; 包楠迪; 樊荣; 迟素敏; 陈景元; 裴建明; 刘亚莉

    2012-01-01

    Freezing cold injury is based on pathological changes of freezing and then melting processes in the injury. Many investigators have confirmed that vascular endothelial cells (VEC) with the barrier and membrane transport functions are larger endocrine organs in the body, which participate in a variety of life activities and play an important role in the balance and stability of the internal environment. VEC in the frostbite process can promote thrombus formation that may result in microcirculatory disturbance and cause irreversible reperfusion injury after blood rewarming and flowing. Mitigating the damage of endothelial cells can reduce the microcirculation thrombosis, thereby reducing the reperfusion injury. As an important vascular growth factor, vascular endothelial growth factor ( VEGF) has some type of protective effect on VEC injury in frostbite. VEGF can provide a new approach for prevention and treatment of frostbite by exerting protective effects on vessels through promoting angiogenesis, inhibiting excessive growth of vascular smooth muscle, and anti-thrombosis or anti-inflammatory functions.%冻结性冷损伤是以组织冻结再融化过程的病理改变为基础的损伤.已经证实,血管内皮细胞(VECs)除有屏障和膜转运功能外,还具有内分泌功能,主动参与了多种生命活动,对维持体内环境的平衡与稳定具有重要作用.冻伤过程中VECs的损伤,可促进微循环血栓形成造成微循环障碍;待到复温后,血液恢复流动又可导致不可逆的再灌注损伤.因此,减轻内皮细胞损伤,可以减少微循环血栓形成,从而减轻再灌注对机体造成的损伤.血管内皮细胞生长因子(VEGF)作为重要的血管生长因子,在冻伤时对VECs损伤具有拮抗作用,可通过促进血管再生、抗血栓形成、抑制血管平滑肌过度生长及抗炎的作用等实现的对血管的保护作用,为临床防治冻伤提供了新的思路.

  18. Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury.

    Directory of Open Access Journals (Sweden)

    Srabani Mitra

    Full Text Available Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1 induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury.

  19. Astrocyte-derived vascular endothelial growth factor stabilizes vessels in the developing retinal vasculature.

    Directory of Open Access Journals (Sweden)

    Andrew Scott

    Full Text Available Vascular endothelial growth factor (VEGF plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans.

  20. DYNAMIC CHANGES OF SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS IN A RAT MYOCARDIAL INFARCTION MODEL

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective. To investigate the dynamic changes of serum vascular endothelial growth factor(VEGF) levels in a rat model of acute myocardial infarction. Materials and methods. Eighty-eight adult male Sprague-Dawley rats weighing approximately 270 g were used in this study. Eighty rats were subjected to left coronary artery ligation, with 8 rats for each different duration of infarct.Eight sham-operated animals in which the left coronary artery was surgically exposed without ligation were used as con-trols. Blood samples were drawn from the right atrium before ( sham animals ) and 1,3,6,12,24 h and 2,3,5,7,14 dafter myocardial infarction. The concentrations of serum VEGF were measured by a sensitive enzyme-linked im munosorbent assay with a rabbit polyclonal antibody specific for VEGF. Results. In the 8 control animals, the mean concentration of serum VEGF was 66.99 ± 17.83 pg/ml. Six hours after myocardial infarction, the level of serum VEGF significantly increased to 125.68 ± 28.07 pg/ml ( P <0.01 vs. sham controls), and reached a peak (240.61 ± 70.63 pg/ml. P <0.01 vs. sham animals) at 24 h after ligation and then decreased gradually over the remaining 2 weeks. However, the level remained significantly elevated for 14 d(107.64±30.13pg/ml, P<0.01 vs. sham controls). Condusion. The present study shows that the levels of serum VEGF are markedly increased until 14 d in the ratmodel of acute myocantial infarction. The increased serum VEGF level may play an important role in the angiogencsisassociated with myocardial infarction.

  1. Assessment of Serum Vascular Endothelial Growth Factor Levels in Pregnancy-Induced Hypertension Patients

    Science.gov (United States)

    Tandon, Vibha; Hiwale, Swati; Amle, Dnyanesh; Nagaria, Tripti

    2017-01-01

    Objective. The objective of the study was to assess the serum vascular endothelial growth factor (VEGF) levels in peripheral blood of patients with pregnancy-induced hypertension (PIH) and find association between serum VEGF levels and PIH. Methods. Thirty-five PIH subjects, 35 normal pregnant females, and 20 normal healthy females were included in the study. Detailed history, clinical examination, and relevant biochemical parameters were assessed; serum VEGF levels were estimated using Double-antibody enzyme-linked immunosorbent assay. Results. The study groups were found to be age matched (p = 0.38). VEGF level in the pregnancy-induced hypertensive group (median = 109.19 (3.38 ± 619)) was significantly higher than the normal pregnant (median = 20.82 (1.7–619)) and control (median = 4.92 (1.13–13.07)) group and the difference between these three groups was significant (p < 0.0001). The 3 groups are found to be significantly different in terms of RBS (p = 0.01), urea (p < 0.0001), creatinine (p = 0.0005), AST (p = 0.0032), ALT (p = 0.0007), total protein (p = 0.0004), albumin (p < 0.0001), calcium (p = 0.001), and sodium (p = 0.02), while no statistically significant difference was found between total bilirubin (p = 0.167), direct bilirubin (p = 0.07), uric acid (p = 0.16), and potassium (p = 0.14). Conclusion. Significantly higher levels of serum VEGF were noted in PIH subjects compared to normal pregnant and control subjects. PMID:28133548

  2. SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN PATIENTS WITH ANGINA PECTORIS AND ACUTE MYOCARDIAL INFARCTION

    Institute of Scientific and Technical Information of China (English)

    尹瑞兴; 冯建章; 陈旦红; 乌汉东

    2000-01-01

    Objective. To determine whether serum vascular endothelial growth factor (VEGF) concontrafions are altered in several kinds of coronary heart disease patients. Materials and methods. Using a VEGF enzyme-linked immunosorbent assay (ELISA), serum VEGF concemra-tions were determined in anteotbital venous blood of 16 patients with stable angina pectoris(SAP), 16 with unstable angina pectoris(UAP) and 16 with acute myocardial infarcfion (AMI) before and after thrombolytic therapy, and d 16 age- and sex-matched healthy volunteers who used as controls. Results. The concentrations of serum VEGF in patients with SAP(98.60 ± 26.99pg/ml) and UAP ( 103.61 ± 24.89pg/ml) tended to be higher than those in control subjects(80.44 ± 24.57pg/ml), but the differences did notreach statistical significance ( P > 0.05 for each). Before thrombolyfie therapy, the concentrations of serum VEGF in patients with AM1 (285.92 ± 125.15pg/ml) were significantly higher than those in patients with SAP, UAP or control subjects ( P < 0.01 ,respectively), and correlated with synchronous serum ereafine kinase (CK) and its MB iscenzyme (CK-MB) contents( r = 0.866, P < 0.001 and r = 0.948, P < 0.001 ;respectively). Three hours after thrombolysis,the concentrations of VEGF had fallen to 111.57 ± 31.29pg/ml ( P < 0.01 vs. before thrombelytie therapy and P <0. 05 vs. control subjects). Condusion. The present study shows that serum concentrafiom of VEGF in patients with AMI are markedly ele-vated and that increased serum VEGF levels may be one of the most sensitive indexes in diagnosing AMI and judging reperfnsion.

  3. SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN PATIENTS WITH ANGINA PECTORIS AND ACUTE MYOCARDIAL INFARCTION

    Institute of Scientific and Technical Information of China (English)

    尹瑞兴; 冯建章; 陈旦红; 乌汉东

    2000-01-01

    Objective. To determine whether serum vascular endothelial growth factor(VEGF)concentrations are altered in several kinds of coronary heart disease patients. Materials and methods. Using a VEGF enzyme-linked immunosorbent assay(ELISA), serum VEGF concentra tions were determined in antecubital venous blood of 16 patients with stable angina pectoris(SAP), 16 with unstable angina pectoris(UAP) and 16 with acute myocardial infarction(AMI) before and after thrombolytic therapy, and of 16 age and sex-matched healthy volunteers who used as controls. Results. The concentrations of serum VEGF in patients with SAP(98.60 ± 26.99pg/ml) and UAP (103.61 ± 24.89pg/ml) tended to be higher than those in control subjects(80.44 ± 24.57pg/ml), but the differences did not reach statistical significance (P > 0.05 for each). Before throm bolytic therapy, the concentrations of serum VEGF in patients with AMI (285.92 ± 125.15pg/ml) were significantly higher than those in patients with SAP, UAP or control subjects ( P < 0.01 ,respectively), and correlated with synchronous serum creatine kinase (CK) and its MB isoenzyme (CK-MB) contents(r=0.866, P < 0.001 and r =0.948,P < 0.001;respectively). Three hours after thrombolysis, the concentrations of VEGF had fallen to 111.57 ± 31.29pg/ml ( P <0.01 vs. before thrombolytic therapy and P< 0.05 vs .control subjects). Conclusion. The present study shows that serum concentrations of VEGF in patients with AMI are markedly ele vated and that increased serum VEGF levels may be one of the most sensitive indexes in diagnosing AMI and judging reperfusion.

  4. Angiogenin and vascular endothelial growth factor expression in lungs of lung cancer patients.

    Science.gov (United States)

    Rozman, Ales; Silar, Mira; Kosnik, Mitja

    2012-12-01

    BACKGROUND.: Lung cancer is the leading cause of cancer deaths. Angiogenesis is crucial process in cancer growth and progression. This prospective study evaluated expression of two central regulatory molecules: angiogenin and vascular endothelial growth factor (VEGF) in patients with lung cancer. PATIENTS AND METHODS.: Clinical data, blood samples and broncho-alveolar lavage (BAL) from 23 patients with primary lung carcinoma were collected. BAL fluid was taken from part of the lung with malignancy, and from corresponding healthy side of the lung. VEGF and angiogenin concentrations were analysed by an enzyme-linked immunosorbent assay. Dilution of bronchial secretions in the BAL fluid was calculated from urea concentration ratio between serum and BAL fluid. RESULTS.: We found no statistical correlation between angiogenin concentrations in serum and in bronchial secretions from both parts of the lung. VEGF concentrations were greater in bronchial secretions in the affected side of the lung than on healthy side. Both concentrations were greater than serum VEGF concentration. VEGF concentration in serum was in positive correlation with tumour size (p = 0,003) and with metastatic stage of disease (p = 0,041). There was correlation between VEGF and angiogenin concentrations in bronchial secretions from healthy side of the lung and between VEGF and angiogenin concentrations in bronchial secretions from part of the lung with malignancy. CONCLUSION.: Angiogenin and VEGF concentrations in systemic, background and local samples of patients with lung cancer are affected by different mechanisms. Pro-angiogenic activity of lung cancer has an important influence on the levels of angiogenin and VEGF.

  5. Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates.

    Science.gov (United States)

    He, Wenwu; Tang, Yanyan; Qi, Bin; Lu, Chuansen; Qin, Chao; Wei, Yunfei; Yi, Jiachao; Chen, Mingwu

    2014-02-10

    Vascular endothelial growth factor (VEGF), known to play an important role in vascular homeostasis, vascular integrity and angiogenesis, is little known about the evolutionary relationship of its five members especially the role of gene duplication and natural selection in the evolution of the VEGF family. In this study, seventy-five full-length cDNA sequences from 33 vertebrate species were extracted from the NCBI's GenBank, UniProt protein database and the Ensembl database. By phylogenetic analyses, we investigated the origin, conservation, and evolution of the VEGFs. Five VEGF family members in vertebrates might be formed by gene duplication. The inferred evolutionary transitions that separate members which belong to different gene clusters correlated with changes in functional properties. Selection analysis and protein structure analysis were combined to explain the relationship of the site-specific evolution in the vertebrate VEGF family. Eleven positive selection sites, one transmembrane region and the active sites were detected in this process.

  6. Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature.

    Science.gov (United States)

    Zhao, Liqing; Wang, Ke; Ferrara, Napoleone; Vu, Thiennu H

    2005-07-01

    The vasculature forms an intrinsic functional component of the lung and its development must be tightly regulated and coordinated with lung epithelial morphogenesis. Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in a complementary pattern in the lungs during embryonic development. VEGF is expressed by epithelium and the receptors in the surrounding mesenchyme. To determine the function of VEGF in lung formation, we inhibited its activity using a soluble receptor in lung renal capsule grafts. Inhibition of VEGF results in inhibition of vascular development and significant alteration in epithelial development. Epithelial proliferation is inhibited, sacculation is impaired, and the epithelium undergoes apoptosis. Interestingly, when VEGF is attenuated, epithelial differentiation still proceeds, as shown by acquisition of both proximal and distal markers. These data show that VEGF co-ordinates epithelial and vascular development. It is required for the development of the lung vasculature and the vasculature is necessary for epithelial proliferation and morphogenesis, but not for cell differentiation.

  7. A Novel Molecular and Functional Stemness Signature Assessing Human Cord Blood-Derived Endothelial Progenitor Cell Immaturity.

    Directory of Open Access Journals (Sweden)

    Oriane Guillevic

    Full Text Available Endothelial Colony Forming Cells (ECFCs, a distinct population of Endothelial Progenitor Cells (EPCs progeny, display phenotypic and functional characteristics of endothelial cells while retaining features of stem/progenitor cells. Cord blood-derived ECFCs (CB-ECFCs have a high clonogenic and proliferative potentials and they can acquire different endothelial phenotypes, this requiring some plasticity. These properties provide angiogenic and vascular repair capabilities to CB-ECFCs for ischemic cell therapies. However, the degree of immaturity retained by EPCs is still confused and poorly defined. Consequently, to better characterize CB-ECFC stemness, we quantified their clonogenic potential and demonstrated that they were reprogrammed into induced pluripotent stem cells (iPSCs more efficiently and rapidly than adult endothelial cells. Moreover, we analyzed the transcriptional profile of a broad gene panel known to be related to stem cells. We showed that, unlike mature endothelial cells, CB-ECFCs expressed genes involved in the maintenance of embryonic stem cell properties such as DNMT3B, GDF3 or SOX2. Thus, these results provide further evidence and tools to appreciate EPC-derived cell stemness. Moreover this novel stem cell transcriptional signature of ECFCs could help better characterizing and ranging EPCs according to their immaturity profile.

  8. Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF) and apoptosis in fetal adrenal glands.

    Science.gov (United States)

    Karaca, T; Hulya Uz, Y; Karabacak, R; Karaboga, I; Demirtas, S; Cagatay Cicek, A

    2015-11-26

    This study investigated the expression of vascular endothelial growth factor (VEGF), vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg) before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0) was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis.

  9. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature.

    Directory of Open Access Journals (Sweden)

    Tony E Walshe

    Full Text Available Pericyte-endothelial cell (EC interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-beta signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-beta signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-beta signaling was inhibited by systemic expression of soluble endoglin (sEng and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-beta signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG. Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-beta signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-beta signaling. These results implicate constitutive TGF-beta signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-beta signaling in vasoproliferative and vascular degenerative retinal diseases.

  10. The soluble guanylyl cyclase inhibitor NS-2028 reduces vascular endothelial growth factor-induced angiogenesis and permeability.

    Science.gov (United States)

    Morbidelli, Lucia; Pyriochou, Anastasia; Filippi, Sandra; Vasileiadis, Ioannis; Roussos, Charis; Zhou, Zongmin; Loutrari, Heleni; Waltenberger, Johannes; Stössel, Anne; Giannis, Athanassios; Ziche, Marina; Papapetropoulos, Andreas

    2010-03-01

    Nitric oxide (NO) is known to promote vascular endothelial growth factor (VEGF)-stimulated permeability and angiogenesis. However, effector molecules that operate downstream of NO in this pathway remain poorly characterized. Herein, we determined the effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in vitro and in vivo. Treatment of endothelial cells (EC) with VEGF stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with the sGC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028) blunted cGMP levels without affecting VEGF-receptor phosphorylation. Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF. In addition, cells in which sGC was inhibited exhibited no migration and sprouting in response to VEGF. To study the mechanisms through which NS-2028 inhibits EC migration, we determined the effects of alterations in cGMP levels on p38 MAPK. Initially, we observed that inhibition of sGC attenuated VEGF-stimulated activation of p38. In contrast, the addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC migration. To test whether sGC also mediated the angiogenic effects of VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028 orally displayed a reduced angiogenic response to VEGF. As increased vascular permeability occurs prior to new blood vessel formation, we determined the effect of NS-2028 in vascular leakage. Using a modified Miles assay, we observed that NS-2028 attenuated VEGF-induced permeability. Overall, we provide evidence that sGC mediates the angiogenic and permeability-promoting activities of VEGF, indicating the significance of sGC as a downstream effector of VEGF-triggered responses.

  11. Perlecan and vascular endothelial growth factor-encoding DNA-loaded chitosan scaffolds promote angiogenesis and wound healing.

    Science.gov (United States)

    Lord, Megan S; Ellis, April L; Farrugia, Brooke L; Whitelock, John M; Grenett, Hernan; Li, Chuanyu; O'Grady, Robert L; DeCarlo, Arthur A

    2017-03-28

    The repair of dermal wounds, particularly in the diabetic population, poses a significant healthcare burden. The impaired wound healing of diabetic wounds is attributed to low levels of endogenous growth factors, including vascular endothelial growth factor (VEGF), that normally stimulate multiple phases of wound healing. In this study, chitosan scaffolds were prepared via freeze drying and loaded with plasmid DNA encoding perlecan domain I and VEGF189 and analyzed in vivo for their ability to promote dermal wound healing. The plasmid DNA encoding perlecan domain I and VEGF189 loaded scaffolds promoted dermal wound healing in normal and diabetic rats. This treatment resulted in an increase in the number of blood vessels and sub-epithelial connective tissue matrix components within the wound beds compared to wounds treated with chitosan scaffolds containing control DNA or wounded controls. These results suggest that chitosan scaffolds containing plasmid DNA encoding VEGF189 and perlecan domain I have the potential to induce angiogenesis and wound healing.

  12. Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells.

    Science.gov (United States)

    Hojo, Y; Ikeda, U; Takahashi, M; Sakata, Y; Takizawa, T; Okada, K; Saito, T; Shimada, K

    2000-08-01

    There is accumulating evidence of complicated interactions among vascular cells, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages, in the regulation of vascular function and remodeling. We have investigated the mechanisms responsible for matrix metalloproteinase (MMP)-1 expression by interactions between monocytes and vascular endothelial cells. THP-1 cells (human monocytic cell line) and human umbilical vein endothelial cells (HUVECs) were cocultured. MMP-1 levels in the culture medium were measured by enzyme-linked immunosorbent assays. Collagenolytic activity in the culture medium was measured by fluorescence labeled-collagen digestion. Immunohistochemistry using an anti-MMP antibody was carried out to determine which types of cell produce MMP-1. The addition of THP-1 cells to HUVECs for 48 h induced increases in MMP-1 levels and collagenolytic activity, which were 5- and 2-fold relative to those of HUVECs alone, respectively. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced MMP-1 production in the cocolture. Immunohistochemical analysis revealed that both types of cell produce MMP-1 in the coculture. Neutralizing anti-interleukin-1 beta and tumor necrosis factor- alpha antibodies inhibited MMP-1 production by the coculture. The Src kinase and MEK inhibitors significantly inhibited MMP-1 production by the coculture. Coculture of THP-1 cells and HUVECs induced significant increases in Src and mitogen activated protein (MAP) kinase activities. Enhanced MMP-1 expression induced by monocyte-endothelial cell interactions may play an important role in the pathogenesis of atherosclerosis and plaque rupture.

  13. Acute Effect of High-Intensity Eccentric Exercise on Vascular Endothelial Function in Young Men.

    Science.gov (United States)

    Choi, Youngju; Akazawa, Nobuhiko; Zempo-Miyaki, Asako; Ra, Song-Gyu; Shiraki, Hitoshi; Ajisaka, Ryuichi; Maeda, Seiji

    2016-08-01

    Choi, Y, Akazawa, N, Zempo-Miyaki, A, Ra, S-G, Shiraki, H, Ajisaka, R, and Maeda, S. Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men. J Strength Cond Res 30(8): 2279-2285, 2016-Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and arterial stiffness after high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 year) performed maximal eccentric elbow flexor exercise using their nondominant arm. Before and 45 minutes after eccentric exercise, carotid arterial compliance and brachial artery FMD and L-FMC in the nonexercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased after eccentric exercise. Brachial FMD was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial L-FMC before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in FMD (r = 0.779; p ≤ 0.05), and a negative correlation was detected between change in β-stiffness index and change in FMD (r = -0.891; p eccentric exercise. In this study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.

  14. In Vivo Vascularization of Endothelial Cells Derived from Bone Marrow Mesenchymal Stem Cells in SCID Mouse Model

    Directory of Open Access Journals (Sweden)

    Allameh Abdolamir

    2016-07-01

    Full Text Available Objective In vivo and in vitro stem cell differentiation into endothelial cells is a promising area of research for tissue engineering and cell therapy. Materials and Methods We induced human mesenchymal stem cells (MSCs to differentiate to endothelial cells that had the ability to form capillaries on an extracellular matrix (ECM gel. Thereafter, the differentiated endothelial cells at early stage were characterized by expression of specific markers such as von Willebrand factor (vWF, vascular endothelial growth factor (VEGF receptor 2, and CD31. In this experimental model, the endothelial cells were transplanted into the groins of severe combined immunodeficiency (SCID mice. After 30 days, we obtained tissue biopsies from the transplantation sites. Biopsies were processed for histopathological and double immunohistochemistry (DIHC staining. Results Endothelial cells at the early stage of differentiation expressed endothelial markers. Hematoxylin and eosin (H&E staining, in addition to DIHC demonstrated homing of the endothelial cells that underwent vascularization in the injected site. Conclusion The data clearly showed that endothelial cells at the early stage of differentiation underwent neovascularization in vivo in SCID mice. Endothelial cells at their early stage of differentiation have been proven to be efficient for treatment of diseases with impaired vasculogenesis.

  15. Fetal exposure to a diabetic intrauterine environment resulted in a failure of cord blood endothelial progenitor cell adaptation against chronic hypoxia

    Science.gov (United States)

    Dincer, U Deniz

    2015-01-01

    Gestational diabetes mellitus (GDM) has long-term health consequences, and fetal exposure to a diabetic intrauterine environment increases cardiovascular risk for her adult offspring. Some part of this could be related to their endothelial progenitor cells (EPCs). Understanding the vessel-forming ability of human umbilical cord blood (HUCB)-derived endothelial colony-forming cells (ECFCs) against pathological stress such as GDM response to hypoxia could generate new therapeutic strategies. This study aims to investigate the role of chronic hypoxia in EPCs functional and vessel-forming ability in GDM subjects. Each ECFC was expressed in endothelial and pro-angiogenic specific markers, namely endothelial nitric oxide synthase (eNOS), platelet (PECAM-1) endothelial cell adhesion molecule 1, vascular endothelial-cadherin CdH5 (Ca-dependent cell adhesion molecule), vascular endothelial growth factor A, (VEGFA) and insulin-like growth factor 1 (IGF1). Chronic hypoxia did not affect CdH5, but PECAM1 MRNA expressions were increased in control and GDM subjects. Control hypoxic and GDM normoxic VEGFA MRNA expressions and hypoxia-inducible factor 1-alpha (HIF1α) protein expressions were significantly increased in HUCB ECFCs. GDM resulted in most failure of HUCB ECFC adaptation and eNOS protein expressions against chronic hypoxia. Chronic hypoxia resulted in an overall decline in HUCB ECFCs’ proliferative ability due to reduction of clonogenic capacity and diminished vessel formation. Furthermore, GDM also resulted in most failure of cord blood ECFC adaptation against chronic hypoxic environment. PMID:25565870

  16. Synergistic effect of angiotensin II on vascular endothelial growth factor-A-mediated differentiation of bone marrow-derived mesenchymal stem cells into endothelial cells

    OpenAIRE

    Ikhapoh, Izuagie Attairu; Pelham, Christopher J; Agrawal, Devendra K.

    2015-01-01

    Introduction Increased levels of angiotensin II (Ang II) and activity of Ang II receptor type 1 (AT1R) elicit detrimental effects in cardiovascular disease. However, the role of Ang II receptor type 2 (AT2R) remains poorly defined. Mesenchymal stem cells (MSCs) replenish and repair endothelial cells in the cardiovascular system. Herein, we investigated a novel role of angiotensin signaling in enhancing vascular endothelial growth factor (VEGF)-A-mediated differentiation of MSCs into endotheli...

  17. Exercise training improves vascular endothelial function in patients with type 1 diabetes.

    Science.gov (United States)

    Fuchsjäger-Mayrl, Gabriele; Pleiner, Johannes; Wiesinger, Günther F; Sieder, Anna E; Quittan, Michael; Nuhr, Martin J; Francesconi, Claudia; Seit, Hans-Peter; Francesconi, Mario; Schmetterer, Leopold; Wolzt, Michael

    2002-10-01

    OBJECTIVE-Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training. RESEARCH DESIGN AND METHODS-The study included 26 patients with type 1 diabetes of 20 +/- 10 years' duration and no overt angiopathy; 18 patients (42 +/- 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 +/- 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N(G)-monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise. RESULTS-Training increased peak oxygen uptake (VO(2max)) by 13% after 2 months and by 27% after 4 months (P = 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 +/- 1.1 to 9.8 +/- 1.1% (P = 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 +/- 0.9% before training and by 13.4 +/- 1.5% after 4 months of training (P = 0.02). VO(2max), FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise. CONCLUSIONS-Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.

  18. Zinc oxide particles induce inflammatory responses in vascular endothelial cells via NF-{kappa}B signaling

    Energy Technology Data Exchange (ETDEWEB)

    Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China); Yeh, Szu-Ching; Tsai, Feng-Yuan; Lin, Ho-Jane [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China); Cheng, Tsun-Jen [Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University, Taipei, Taiwan (China); Chao, How-Ran [Department of Environmental Science and Engineering, National Pingtung University of Science and Technology, Neipu, Pingtung, Taiwan (China); Tai, Lin-Ai [Center for Nanomedicine Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China)

    2010-11-15

    This study investigated inflammatory effects of zinc oxide (ZnO) particles on vascular endothelial cells. The effects of 50 and 100-nm ZnO particles on human umbilical vein endothelial cells (HUVECs) were characterized by assaying cytotoxicity, cell proliferation, and glutathione levels. A marked drop in survival rate was observed when ZnO concentration was increased to 45 {mu}g/ml. ZnO concentrations of {<=}3 {mu}g/ml resulted in increased cell proliferation, while those of {<=}45 {mu}g/ml caused dose-dependent increases in oxidized glutathione levels. Treatments with ZnO concentrations {<=}45 {mu}g/ml were performed to determine the expression of intercellular adhesion molecule-1 (ICAM-1) protein, an indicator of vascular endothelium inflammation, revealing that ZnO particles induced a dose-dependent increase in ICAM-1 expression and marked increases in NF-{kappa}B reporter activity. Overexpression of I{kappa}B{alpha} completely inhibited ZnO-induced ICAM-1 expression, suggesting NF-{kappa}B plays a pivotal role in regulation of ZnO-induced inflammation in HUVECs. Additionally, TNF-{alpha}, a typical inflammatory cytokine, induced ICAM-1 expression in an NF-{kappa}B-dependent manner, and ZnO synergistically enhanced TNF-{alpha}-induced ICAM-1 expression. Both 50 and 100-nm ZnO particles agglomerated to similar size distributions. This study reveals an important role for ZnO in modulating inflammatory responses of vascular endothelial cells via NF-{kappa}B signaling, which could have important implications for treatments of vascular disease.

  19. In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment.

    Science.gov (United States)

    Tattersall, Ian W; Du, Jing; Cong, Zhuangzhuang; Cho, Bennet S; Klein, Alyssa M; Dieck, Chelsea L; Chaudhri, Reyhaan A; Cuervo, Henar; Herts, James H; Kitajewski, Jan

    2016-04-01

    Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.

  20. Three Cases of Organized Hematoma of the Maxillary Sinus: Clinical Features and Immunohistological Studies for Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor 2 Expressions

    Directory of Open Access Journals (Sweden)

    Shoichiro Imayoshi

    2015-01-01

    Full Text Available Objectives. Organized hematoma (OH is a rare, nonneoplastic, hemorrhagic lesion causing mucosal swelling and bone thinning, mainly in the maxillary sinus. We aimed to clarify the clinical presentation and treatment of OH. Methods. Three cases of maxillary sinus OH and a literature review are presented. Results. Three men aged 16–40 years complained of nasal obstruction, frequent epistaxis, and/or headache. Clinical and radiological examinations revealed a maxillary sinus OH. They were cured in a piecemeal fashion via endoscopic middle meatal antrostomy. Furthermore, vascular endothelial growth factor and its receptor were expressed in the lesion. Conclusions. The pathogenesis of OH is unclear and it presents various histological and imaging findings; however, it is not difficult to rule out malignant tumors. Minimally invasive surgery such as endoscopic sinus surgery can cure it completely. Thus, it is important to determine the diagnosis using CT and MRI and to quickly provide surgical treatment.

  1. Effects of overfeeding in breastfeeding period on blood pressure and vascular endothelial dilation function of rats%哺乳期过度营养对大鼠血压及血管内皮舒张功能的影响

    Institute of Scientific and Technical Information of China (English)

    刘娟; 陈梦莹; 戴焱焱; 夏冬晴; 周楠; 计晨琳; 李晓南

    2015-01-01

    Objective To study the effects of postnatal overfeeding and high-fat diet on blood pressure of rats,and to explore the pathophysiological mechanism underlying hypertension induced by continuous early postnatal overfeeding.Methods Male Sprague-Dawley rats were randomly divided into normal feeding group (10/litter) and overfeeding group (3/litter) on postnatal day 3 with a random number table.After weaning at postnatal week 3,the rats were randomly given standard chow or high-fat (HF) diet until week 16.Hence four groups were analyzed,namely normal feeding group,breastfed overfeeding group,post-weaning overfeeding group,and continuous overfeeding group.Body weight was continuously monitored in each week.Visceral fat pad (retroperitoneal and perigenital),systolic pressure,and heart rate were observed at week 3 and week 16.Thoracic aorta was sampled for measurement of vascular endothelial dilation function.Histological morphology was observed with HE staining,nitric oxide content of thoracic aorta was detected with nitrate reductase method.The mRNA expression of endothelial nitric oxide synthase (eNOS) in thoracic aorta was determined by real-time polymerase chain reaction.The protein expressions of eNOS and phosphorylated eNOS were determined by Western blot.Results At week 3,breastfed overfeeding rats displayed significantly larger body weight [(77.80 ± 0.57) g vs.(62.80 ±0.85) g,t =14.576,P < 0.01] and visceral fat [retroperitoneal:(8.19 ± 0.49) mg/g vs.(4.92 ± 0.31) mg/g,t =5.629,P<0.01;perigenital:(3.50 ±0.29) mg/g vs.(2.08 ±0.13) mg/g,t =4.552,P <0.01] compared with normal feedindg rats,and the protein expression of phosphorylated eNOS in aortic tissues was significantly reduced to week 16 (F =15.215,P <0.01);high-fat diet feeding after weaning further increased the body weight and fat mass in breastfed overfeeding rats.At week 16,continuous overfeeding rats showed hypertension [(149 ± 1.94) mmHg (1 mmHg =0.133 kPa),F =22.834,P <0.01],impaired

  2. Effect of Therapy of Clearing Heat, Nourishing Yin and Activating Blood on the Expression of Vascular Endothelial Growth Factor in Heart and Its Ultrastructure of Diabetic Rats%清热养阴活血法对糖尿病大鼠心肌细胞VEGF表达和超微结构的影响

    Institute of Scientific and Technical Information of China (English)

    戴红

    2011-01-01

    目的:观察清热养阴活血方剂逐瘀化消饮对DM大鼠心脏VEGF表达和心肌细胞超微结构的影响.方法:采用β - cytotoxins大鼠模型,将Wistar大鼠随机分为正常组、模型组、胰岛素组、逐瘀化消饮低、中、高剂量+胰岛素组,观察糖尿病大鼠在胰岛素控制血糖基本一致的情况下,逐瘀化消饮治疗8周,用免疫组化方法检测DM大鼠心肌组织VEGF的分布状况,用H-600透射电镜观察心肌细胞的超微结构.结果:与胰岛素组相比,逐瘀化消饮能抑制DM大鼠心肌VEGF的表达,有效地保护心肌细胞的超微结构.结论:逐瘀化消饮通过多种机制来有效地抑制DM大鼠心脏微血管病变的发生发展,这可能是其防治DM大鼠心脏微血管病变发生发展的机理之一.%Objective: To observe the effect on the expression of vascular endothelial growth factor in heart and its ul-trastructure of diabetic rats by method of clearing heat, nourishing yin and activating blood. Methods:The model rats of diabetes mellitus(DM) was induced by β -cytotoxins. Apart from the control groups, all the model rats were randomly divided into five groups,the pathology group, the insulin group, the low dose ZYHXY and insulin group(ZYHXY -L), the middle dose ZYHXY and insulin group( ZYHXY - M) , the high dose ZYHXY and insulin group( ZYHXY - H). On the condition all the model rats had the same blood glucose controlled by insulin, observing the effect on the expression of VEGF in heart and its ultrastructure with electron microscope after treated eight weeks by ZYHXY. Results: In comparing with the insulin groups, the low, middle, high dose groups of ZYHXY have the significant difference( P <0.05) in inhibiting the experession of VEGF in heart, and effectively protecting myocardiac ultrastructure. Conclusion.; ZYHXY can prevent the development of angiopathy of heart through many aspects, which is probably one of treatment and prevention mechanisms of the diabetic

  3. A vascular endothelial growth factor activating transcription factor increases the endothelial progenitor cells population and induces therapeutic angiogenesis in a type 1 diabetic mouse with hindlimb ischemia

    Institute of Scientific and Technical Information of China (English)

    Diao Yongpeng; Lian Lishan; Guo Lilong; Chen Houzao; Chen Yuexin; Song Xiaojun; Li Yongjun

    2014-01-01

    Background Therapeutic angiogenesis has been shown to promote blood vessel growth and improve tissue perfusion.Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis.However,it has side effects that limit its therapeutic utility in vivo,especially at high concentrations.This study aimed to investigate whether an intramuscular injection of a genetically engineered zinc finger VEGF-activating transcription factor modulates the endothelial progenitor cells (EPC) and promotes therapeutic angiogenesis in a hindlimb ischemia model with type 1 diabetes.Methods Alloxan (intravenous injection) was used to induce type Ⅰ diabetes in C57BL/6 mice (n=58).The ischemic limb received ZFP-VEGF (125 μg ZFP-VEGF plasmid in 1% poloxamer) or placebo (1% poloxamer) intramuscularly.Mice were sacrificed 3,5,10,or 20 days post-injection.Limb blood flow was monitored using laser Doppler perfusion imaging.VEGF mRNA and protein expression were examined using real-time PCR and ELISA,respectively.Capillary density,proliferation,and apoptosis were examined using immunohistochemistry techniques.Flow cytometry was used to detect the EPC population in bone marrow.Two-tailed Student's paired t test and repeated-measures analysis of variance were used for statistical analysis.Results ZFP-VEGF increased VEGF mRNA and protein expression at 3 and 10 days post-injection,and increased EPC in bone marrow at day 5 and 20 post-injection compared with controls (P<0.05).ZFP-VEGF treatment resulted in better perfusion recovery,a higher capillary density and proliferation,and less apoptosis compared with controls (P<0.05).Conclusions Intramuscular ZFP-VEGF injection promotes therapeutic angiogenesis in an ischemic hindlimb model with type 1 diabetes.This might be due to the effects of VEGF on cell survival and EPC recruitment.

  4. Visualizing the Acute Effects of Vascular-Targeted Therapy In Vivo Using Intravital Microscopy and Magnetic Resonance Imaging: Correlation with Endothelial Apoptosis, Cytokine Induction, and Treatment Outcome

    Directory of Open Access Journals (Sweden)

    Mukund Seshadri

    2007-02-01

    Full Text Available The acute effects of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA were investigated in vivo using intravital microscopy (IVM and magnetic resonance imaging (MRI. Changes in vascular permeability and blood flow of syngeneic CT-26 murine colon adenocarcinomas were assessed at 4 and 24 hours after DMXAA treatment (30 mg/kg, i.p. and correlated with induction of tumor necrosis factor-α (TNF-α, endothelial damage [CD31/terminal deoxynucleotidyl transferase (TdT], and treatment outcome. Intravital imaging revealed a marked increase in vascular permeability 4 hours after treatment, consistent with increases in intratumoral mRNA and protein levels of TNF-α. Parallel contrast-enhanced MRI studies showed a ~ 4-fold increase in longitudinal relaxation rates (ΔR1, indicative of increased contrast agent accumulation within the tumor. Dualimmunostained tumor sections (CD31/TdT revealed evidence of endothelial apoptosis at this time point. Twenty-four hours after treatment, extensive hemorrhage and complete disruption of vascular architecture were observed with IVM, along with a significant reduction in ΔR1 and virtual absence of CD31 immunostaining. DMXAA-induced tumor vascular damage resulted in significant long-term (60-day cures compared to untreated controls. Multimodality imaging approaches are useful in visualizing the effects of antivascular therapy in vivo. Such approaches allow cross validation and correlation of findings with underlying molecular changes contributing to treatment outcome.

  5. Testosterone Enhances the Proliferation of Peripheral-Blood-Derived Endothelial Progenitor Cells by up-regulating Vascular Endothelial Growth Factor Expression%睾酮通过上调血管内皮生长因子表达促进外周血内皮祖细胞增殖

    Institute of Scientific and Technical Information of China (English)

    薛亚威; 任国庆; 王芝; 孙文文; 张浩

    2013-01-01

    目的 探讨雄激素对外周血内皮祖细胞(PB-EPC,)增殖能力的影响及其可能机制.方法 将健康志愿者外周血经密度梯度离心法分离的单个核细胞接种至人纤维连接蛋白包被的培养板中,EGM-2MV培养7天后,多波长激光共聚焦显微镜鉴定FITC标记的荆豆凝集素和Dil标记的乙酰化低密度脂蛋白双染色阳性为PB-EPC.将贴壁细胞分为5组,前4组分别加入0、1、10、100nmol/L睾酮,第5组加入10 nmol/L雄激素受体阻断剂氟他胺干预3h后,再加10 nmol/L睾酮干预.培养48 h后,MTT比色法检测各组PB-EPC的增殖能力.实时定量PCR检测血管内皮生长因子(VEGF) mRNA的表达变化,ELISA检测VEGF分泌量的变化.结果 睾酮呈浓度依赖性促进EPC增殖,雄激素受体阻断剂氟他胺完全阻断睾酮对EPC的促进作用.与空白对照组相比,睾酮在mRNA和蛋白水平上调PB-EPC的VEGF表达,氟他胺可阻断此作用.结论 睾酮通过雄激素受体途径上调VEGF的表达,促进PB-EPC增殖.%Aim To explore the effects and related mechanisms of testosterone on the proliferation of Peripheral-blood endothelial progenitor cells (PB-EPCs). Methods Total mononuclear cells(MNC) were isolated from peripheral blood of healthy volunteers by Ficoll density gradient centrifugation, culturing with EGM-2MV for 7 days in vitro. The adherent cells showed up taking of acetylated low-density ( ac-LDL-Dil) and binding of lectin ( FITC-UEA-I) , observing with confocal laser scanning microscopy. PB-EPC were dealt with four concentrations of testosterone, as 0 nmol/L, 1 nmol/L, 10 nmol/L,and 100 nmol/L respectively, and in another group PB-EPC were pretreated with 10 nmol/L flutamide (androgen receptor antagonist) for 3h and then stimulated with 10 nmol/L testosterone. After 48 h, the ability of cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diph-phenyltetrazolium bromide assay ( MTT). The VEGF expression was tested by quantitative real

  6. C-peptide protects against hyperglycemic memory and vascular endothelial cell apoptosis.

    Science.gov (United States)

    Bhatt, Mahendra Prasad; Lee, Yeon-Ju; Jung, Se-Hui; Kim, Yong Ho; Hwang, Jong Yun; Han, Eun-Taek; Park, Won Sun; Hong, Seok-Ho; Kim, Young-Myeong; Ha, Kwon-Soo

    2016-10-01

    C-peptide exerts protective effects against diabetic complications; however, its role in inhibiting hyperglycemic memory (HGM) has not been elucidated. We investigated the beneficial effect of C-peptide on HGM-induced vascular damage in vitro and in vivo using human umbilical vein endothelial cells and diabetic mice. HGM induced apoptosis by persistent generation of intracellular ROS and sustained formation of ONOO(-) and nitrotyrosine. These HGM-induced intracellular events were normalized by treatment with C-peptide, but not insulin, in endothelial cells. C-peptide also inhibited persistent upregulation of p53 and activation of mitochondrial adaptor p66(shc) after glucose normalization. Further, C-peptide replacement therapy prevented persistent generation of ROS and ONOO(-) in the aorta of diabetic mice whose glucose levels were normalized by the administration of insulin. C-peptide, but not insulin, also prevented HGM-induced endothelial apoptosis in the murine diabetic aorta. This study highlights a promising role for C-peptide in preventing HGM-induced intracellular events and diabetic vascular damage.

  7. Effect of Ligustrazine Injection on Vascular Endothelial Cell of The Patients with Arteriosclerosis Obliterans

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the effect of ligustrazine injection (LI) on vascular endothelial cell of the patients with arteriosclerosis obliterans (ASO) and explore the new pathway of investigating effective vascular protective agents in Chinese medicinal herbs. Methods: Forty-six patients with ASO in the LI group treated by LI were observed, their circulating endothelial cells (CEC) were detected quantitatively before and after treatment. The results were compared with the CEC of 53 cases of healthy persons (control group) in the same period. Results: In the LI group, the immediate cure rate was 45.7% (21 cases), markedly effective rate 36.9% (17 cases) and the effective rate 17.4% (8 cases). The CEC of patients before treatment was 4.39±1.76/0.9μl, which was significantly higher than that of the healthy persons (1.53±0.42/0.9μl). It could be reduced after treatment, along with the improvement of symptoms and signs, to 2.43±0.87/0.9μl, P<0.01. Conclusion: LI in treating ASO not only displays extraordinary effect, but also has good effect in curing the damage of endothelial cells.

  8. Enhanced Viability of Endothelial Colony Forming Cells in Fibrin Microbeads for Sensor Vascularization

    Directory of Open Access Journals (Sweden)

    Jarel K. Gandhi

    2015-09-01

    Full Text Available Enhanced vascularization at sensor interfaces can improve long-term function. Fibrin, a natural polymer, has shown promise as a biomaterial for sensor coating due to its ability to sustain endothelial cell growth and promote local vascularization. However, the culture of cells, particularly endothelial cells (EC, within 3D scaffolds for more than a few days is challenging due to rapid loss of EC viability. In this manuscript, a robust method for developing fibrin microbead scaffolds for long-term culture of encapsulated ECs is described. Fibrin microbeads are formed using sodium alginate as a structural template. The size, swelling and structural properties of the microbeads were varied with needle gauge and composition and concentration of the pre-gel solution. Endothelial colony-forming cells (ECFCs were suspended in the fibrin beads and cultured within a perfusion bioreactor system. The perfusion bioreactor enhanced ECFCs viability and genome stability in fibrin beads relative to static culture. Perfusion bioreactors enable 3D culture of ECs within fibrin beads for potential application as a sensor coating.

  9. Cytokine-Induced Cell Surface Expression of Adhesion Molecules in Vascular Endothelial Cells In vitro

    Institute of Scientific and Technical Information of China (English)

    陈红辉; 刘昌勤; 孙圣刚; 梅元武; 童萼塘

    2001-01-01

    Regulation of the adhesion molecules expression by cytokine in vascular endothelial cells was investigated. Human umbilical vein endothelial cells (HUVEC) were stimulated with cytokines, TNF-α (1-250 U/ml) or IL-1β (0.1-50 U/ml) for 24 h. HUVEC were also cultured with cytokines, TNF-α (100 U/ml) or IL-1β (10 U/ml), for 4-72 h, cell surface expression of adhesion molecules (ICAM-1 and VCAM-1) were detected and quantitated by immunocytochemical methods and computerized imaging analysis technique. Adhesion molecules expression were up-regulated by TNF-α, IL-1β in a concentration- and time-dependent manner. Some significant differences were observed between the effects of cytokines on the ICAM-1 and on VCAM-1 expression. Cytokines might directly induce the expression of ICAM-1 and VCAM-1 in vascular endothelial cells. Our observations indicate differential functions of the two adhesion molecules during the evolution of inflammatory responses in stroke.

  10. Understanding the effects of mature adipocytes and endothelial cells on fatty acid metabolism and vascular tone in physiological fatty tissue for vascularized adipose tissue engineering.

    Science.gov (United States)

    Huber, Birgit; Volz, Ann-Cathrin; Kluger, Petra J

    2015-11-01

    Engineering of large vascularized adipose tissue constructs is still a challenge for the treatment of extensive high-graded burns or the replacement of tissue after tumor removal. Communication between mature adipocytes and endothelial cells is important for homeostasis and the maintenance of adipose tissue mass but, to date, is mainly neglected in tissue engineering strategies. Thus, new co-culture strategies are needed to integrate adipocytes and endothelial cells successfully into a functional construct. This review focuses on the cross-talk of mature adipocytes and endothelial cells and considers their influence on fatty acid metabolism and vascular tone. In addition, the properties and challenges with regard to these two cell types for vascularized tissue engineering are highlighted.

  11. Correlation between CT perfusion parameters and microvessel density and vascular endothelial growth factor in adrenal tumors.

    Directory of Open Access Journals (Sweden)

    Hai-yan Qin

    Full Text Available We evaluated the correlation between computed tomography (CT perfusion parameters and markers of angiogenesis in adrenal adenomas and non-adenomas to determine if perfusion CT can be used to distinguish between them. Thirty-four patients with pathologically-confirmed adrenal tumors (17 adenomas, 17 non-adenomas received CT perfusion imaging before surgery. CT perfusion parameters (blood flow [BF], blood volume [BV], mean transit time [MTT], and permeability surface area product [PS] were calculated. Tumor tissue sections were examined with immunohistochemical methods for vascular endothelial growth factor (VEGF expression and microvessel density (MVD. The mean age of the 34 patients was 43 years. The median BV was significantly higher in adenomas than in non-adenomas [12.3 ml/100 g, inter-quartile range (IQR: 10.4 to 16.5 ml/100 g vs. 8.8 ml/100 g, IQR: 3.3 to 9.4 ml/100 g, p=0.001]. Differences in BF, MTT, and PS parameter values between adenomas and non-adenomas were not significant (p>0.05. The mean MVD was significantly higher in adenomas compared to non-adenomas (98.5 ± 28.5 vs. 53.5 ± 27.0, p<0.0001. Adenomas also expressed significantly higher median VEGF than non-adenomas (65%, IQR: 50 to 79% vs. 45%, IQR: 35 to 67%, p=0.02. A moderately strong correlation between BF and VEGF (r=0.53, p=0.03 and between BV and MVD among adenomas (r=0.57, p=0.02 exist. Morphology, MVD, and VEGF expression in adenomas differ significantly from non-adenomas. Of the CT perfusion parameters examined, both BF and BV correlate with MVD, but only BF correlates with VEGF, and only in adenomas. The significant difference in BV suggests that BV may be used to differentiate adenomas from non-adenomas. However, the small difference in BV shows that it may only be possible to use BV to identify adenomas vs. non-adenomas at extreme BV values.

  12. REGULATING EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANGⅡ ON FROG'S PERICARDIAL STOMATA, MESOTHELIUM AND ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To observe the regulating effects of vascular endothelial growth factor (VEGF) and angiotensinⅡ (ANG II) on the frog's pericardium, lymphatic stomata and angiogenesis so as to reveal their effects and mechanism on the mesothelial permeability, lymphatic stoma regulation and myocardial hypertrophy. Methods. VEGF and ANGⅡ were injected into the frog's peritoneal cavity so as to examine the changes of the pericardial stromata by using transmission electron microscopy, scanning electron microscopy and computerized imaging analysis. Results. Scattered distributed pericardial stomata were found on the parietal pericardium of the frog with a few sinusoid mesothelial cells, whose blood supply was directly from the cardiac chambers flowing into the trabecular spaces of the myocardium (because there are no blood vessels in the myocardium of the frog). The average diameters of the pericardial stomata in VEGF and ANGⅡ groups were 1.50 μ m and 1.79 μ m respectively, which were much larger than those in the control group (0.72 μ m, P< 0.01); the average distribution densities of the stomata were 8.25/0.1 mm2 and 12.80/0.1 mm2 in VEGF and ANGⅡ groups, which were also much higher than those in the control group (3.57/0.1 mm2, P< 0.01); the sinusoid areas in VEGF and ANGⅡ groups were 2442.95 μ m2/0.1 mm2 and 2121.79 μ m2/0.1 mm2, which were larger than that in the control group (995.08 μ m2 /0.1 mm2 , P< 0.01); no angiogenesis was found in the frogs of the experimental groups. Conclusions. VEGF and ANGⅡ could strongly regulate the pericardial stomata by increasing their numbers and openings with larger diameters and higher distribution density. They could also increase the sinusoid areas with the result of the higher permeability of the pericardium, which clearly indicated that VEGF and ANGⅡ could speed up the material transfer of the pericardial cavity and play an important role in preventing myocardial interstitial edema. Yet there was no strong

  13. The development of blood-retinal barrier during the interaction of astrocytes with vascular wall cells

    Institute of Scientific and Technical Information of China (English)

    Huanling Yao; Tianshi Wang; Jiexin Deng; Ding Liu; Xiaofei Li; Jinbo Deng

    2014-01-01

    Astrocytes are intimately involved in the formation and development of retinal vessels. Astrocyte dysfunction is a major cause of blood-retinal barrier injury and other retinal vascular diseases. In this study, the development of the retinal vascular system and the formation of the blood-ret-inal barrier in mice were investigated using immunolfuorescence staining, gelatin-ink perfusion, and transmission electron microscopy. The results showed that the retinal vascular system of mice develops from the optic disc after birth, and radiates out gradually to cover the entire retina, taking the papilla optica as the center. First, the superifcial vasculature is formed on the inner retinal layer;then, the vasculature extends into the inner and outer edges of the retinal inner nuclear layer, forming the deep vasculature that is parallel to the superifcial vasculature. The blood-retinal barrier is mainly composed of endothelium, basal lamina and the end-feet of astrocytes, which become mature during mouse development. Initially, the naive endothelial cells were immature with few organelles and many microvilli. The basal lamina was uniform in thickness, and the glial end-feet surrounded the outer basal lamina incompletely. In the end, the blood-retinal barrier matures with smooth endothelia connected through tight junctions, rela-tively thin and even basal lamina, and relatively thin glial cell end-feet. These ifndings indicate that the development of the vasculature in the retina follows the rules of“center to periphery”and“superifcial layer to deep layers”. Its development and maturation are spatially and tempo-rally consistent with the functional performance of retinal neurons and photosensitivity. The blood-retinal barrier gradually becomes mature via the process of interactions between astro-cytes and blood vessel cells.

  14. The Mechanical Study of Vascular Endothelial Growth Factor on the Prevention of Restenosis after Angioplasty

    Institute of Scientific and Technical Information of China (English)

    LIU Qigong; LU Zaiying; ZHOU Honglian; YAN Jin; ZHANG Weidong

    2001-01-01

    The mechanism of vascular endothelial growth factor (VEGF) on the prevention of restenosis after angioplasty was investigated. The cultured vascular endothelial cells (VEC) were incubated with the conditioned medium (CM) from vascular smooth muscle cells (VSMC) infected with recombinant adenoviruses containing the hVEGF165 gene. To observe the effects of VEGF on proliferation and NO, ET, 6-keto-PGF1α secretion of VEC, WST-1 method, Griess method and radioimmunoassay were used respectively. The PDGF-B mRNA transcription in VECs was detected by RT-PCR. It was showed that NO, 6-keto-PGF1α and OD value were markedly increased in a dosedependent manner in the VEGF-treated groups as compared with those in the control group, while ET and PDGF-B mRNA were significantly decreased in the VEGF-treated groups (P<0. 05 or P<0. 01). Adenovirus vector mediated hVEGF165 gene could promote the proliferation of VECs and im prove NO, PGI2 secretion, inhibit ET secretionand PDGF-B mRNA transcription in the VECs. Theabove results offered further theoretical evidence for VEGF on the prevention of restenosis after angioplasty.

  15. Disturbance of copper homeostasis is a mechanism for homocysteine-induced vascular endothelial cell injury.

    Directory of Open Access Journals (Sweden)

    Daoyin Dong

    Full Text Available Elevation of serum homocysteine (Hcy levels is a risk factor for cardiovascular diseases. Previous studies suggested that Hcy interferes with copper (Cu metabolism in vascular endothelial cells. The present study was undertaken to test the hypothesis that Hcy-induced disturbance of Cu homeostasis leads to endothelial cell injury. Exposure of human umbilical vein endothelial cells (HUVECs to concentrations of Hcy at 0.01, 0.1 or 1 mM resulted in a concentration-dependent decrease in cell viability and an increase in necrotic cell death. Pretreatment of the cells with a final concentration of 5 µM Cu in cultures prevented the effects of Hcy. Hcy decreased intracellular Cu concentrations. HPLC-ICP-MS analysis revealed that Hcy caused alterations in the distribution of intracellular Cu; more Cu was redistributed to low molecular weight fractions. ESI-Q-TOF detected the formation of Cu-Hcy complexes. Hcy also decreased the protein levels of Cu chaperone COX17, which was accompanied by a decrease in the activity of cytochrome c oxidase (CCO and a collapse of mitochondrial membrane potential. These effects of Hcy were all preventable by Cu pretreatment. The study thus demonstrated that Hcy disturbs Cu homeostasis and limits the availability of Cu to critical molecules such as COX17 and CCO, leading to mitochondrial dysfunction and endothelial cell injury.

  16. [Medical significance of endothelial glycocalyx. Part 2: Its role in vascular diseases and in diabetic complications].

    Science.gov (United States)

    Frati Munari, Alberto C

    2014-01-01

    Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. Shredding of glycocalyx appears as an essential initial step in the pathophysiology of atherosclerosis and microangiopathic complications of diabetes mellitus, as well as in chronic venous disease. Atherosclerosis risk factors, as hypercholesterolemia (LDL), hyperglycemia, inflammation, salt excess and altered shear stress can damage glycocalyx. This lead to endothelial dysfunction and allows LDL and leukocytes to filtrate to the subendothelial space initiating atheroma plaque formation. Degradation of glycocalyx in diabetes mellitus is mainly due to oxidative stress and enables protein filtration (albuminuria) and endothelial disorder of microangiopathy. Chronic venous hypertension brings to altered shears stress which results in shredded glycocalyx, this allows leukocytes to migrate into venous wall and initiate inflammation leading to morphologic and functional venous changes of the chronic venous disease. Treatment with glycosaminoglycans (sulodexide) prevents or recovers the damaged glycocalyx and several of its consequences. This drug improves chronic venous disease and promotes healing of chronic venous ulcers. It has also been useful in peripheral arterial obstructive disease and in diabetic nephropathy with albuminuria.

  17. Human vascular smooth muscle cells and endothelial cells cocultured on polyglycolic acid (70/30) scaffold in tissue engineered vascular graft

    Institute of Scientific and Technical Information of China (English)

    WEN Shao-jun; ZHAO Li-min; WANG Shen-guo; LI Jing-xing; CHEN Hua-ying; LIU Jie-lin; LIU Ya; LUO Yi; Roo Changizi

    2007-01-01

    Background Current prosthetic, small diameter vascular grafts showing poor long term patency rates have led to the pursuit of other biological materials. Biomaterials that successfully integrate into surrounding tissue should match not only the mechanical properties of tissues, but also topography. Polyglycolic acid (70/30) has been used as synthetic grafts to determine whether human vascular smooth muscle cells and endothelial cells attach, survive and secrete endothelin and 6-keto-prostaglandin F1α (6-keto-PGF1α).Methods Endothelial cells and smooth muscle cells were isolated from adult human great saphenous vein. They were seeded on polyglycolic acid scaffold in vitro separately to grow vascular patch (Groups A and B respectively) and cocultured in vitro to grow into vascular patch (Group C). Smooth muscle cells and endothelial cells were identified by immunohistochemical analysis and growth of cells on polyglycolic acid was investigated using scanning electron microscopy. The levels of endothelin and 6-keto-PGF1α in the culturing solutions were examined by radioimmunology to measure endothelial function.Results Seed smooth muscle cells adhered to polyglycolic acid scaffold and over 28 days grew in the interstices to form a uniform cell distribution throughout the scaffold. Then seed endothelial cells formed a complete endothelial layer on the smooth muscle cells. The levels of endothelin and 6-keto-prostaglandin F1 alpha in the culturing solution were (234±29) pg/ml and (428+98) pg/ml respectively in Group C and (196+30) pg/ml and (346±120) pg/ml in Group B; both significantly higher than in Groups A and D (blank control group, all P<0.05 ).Conclusions Cells could be grown successfully on polyglycolic acid and retain functions of secretion. Our next step is to use human saphenous vein smooth muscle cells and endothelial cells to grow tubular vascular grafts in vitro.

  18. Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Marcelo Mendonça Mota

    2014-07-01

    Full Text Available Background: Resistance exercise effects on cardiovascular parameters are not consistent. Objectives: The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Methods: Wistar rats were divided into three groups: control group (n = 8; sedentary diabetic (n = 8; and trained diabetic (n = 8. Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. Results: A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2% and an increase in the trained diabetic group (95 ± 3% without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05 in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05 in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg as compared to the sedentary diabetic group. Conclusions: Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats.

  19. Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats

    Energy Technology Data Exchange (ETDEWEB)

    Mota, Marcelo Mendonça; Silva, Tharciano Luiz Teixeira Braga da; Fontes, Milene Tavares; Barreto, André Sales; Araújo, João Eliakim dos Santos [Departamento de Fisiologia - Universidade Federal de Sergipe (UFS), São Cristóvão, SE (Brazil); Oliveira, Antônio Cesar Cabral de; Wichi, Rogério Brandão [Departamento de Educação Física - UFS, São Cristóvão, SE (Brazil); Santos, Márcio Roberto Viana, E-mail: marciorvsantos@bol.com.br [Departamento de Fisiologia - Universidade Federal de Sergipe (UFS), São Cristóvão, SE (Brazil)

    2014-07-15

    Resistance exercise effects on cardiovascular parameters are not consistent. The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2%) and an increase in the trained diabetic group (95 ± 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg) as compared to the sedentary diabetic group. Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats.

  20. Macromolecular depletion modulates the binding of red blood cells to activated endothelial cells.

    Science.gov (United States)

    Yang, Yang; Koo, Stephanie; Lin, Cheryl Shuyi; Neu, Björn

    2010-09-01

    Adhesion of red blood cells (RBCs) to endothelial cells (ECs) is usually insignificant but an enhanced adhesion has been observed in various diseases associated with vascular complications. This abnormal adhesion under pathological conditions such as sickle cell disease has been correlated with increased levels of various plasma proteins but the detailed underlying mechanism(s) remains unclear. Usually it is assumed that the proadhesive effects of plasma proteins originate from ligand interactions cross-linking receptors on adjacent cells, but explicit results detailing binding sites or receptors for some proteins (e.g., fibrinogen) on either RBC or EC surfaces that would support this model are missing. In this study, the authors tested whether there is an alternative mechanism. Their results demonstrate that dextran 2 MDa promotes the adhesion of normal RBCs to thrombin-activated ECs and that this effect becomes more pronounced with increasing thrombin concentration or with prolonged thrombin incubation time. It is concluded that depletion interaction originating from nonadsorbing macromolecules (i.e., dextran) can modulate the adhesion of red blood cells to thrombin-activated EC. This study thereby suggests macromolecular depletion as an alternative mechanism for the adhesion-promoting effects of nonadsorbing plasma proteins. These findings should not only aid in getting a better understanding of diseases associated with vascular complications but should also have many potential applications in biomedical or biotechnological areas that require the control of cell-cell or cell surface interactions.

  1. 不同药物干预对高血压前期患者血管内皮功能及血压的影响%Influence of different drug interventions on vascular endothelial function and blood pressure in patients with prehyper-tension

    Institute of Scientific and Technical Information of China (English)

    江金锋; 林修; 陈闽明; 饶华经

    2015-01-01

    Objective To discuss the influence of different drug interventions on the vascular endothelial function and blood pressure in the patients with prehypertension. Methods Totally 300 cases of newly diagnosed prehypertension from the in-patients in the internal medicine department or individuals undergoing the physical examination in the outpatient department of our hospital were from March to August 2013 selected and divided into 3 groups by screening exclusion. (1)The life intervention group(95 cases) was performed the giving up smoking,limiting drinking wine,sticking to a moderate amount of physical labor,ap-propriate limit the intake of salt and fat add,and controlling the body mass;(2)the candesartan group(94 cases) was added with candesartan 4 mg/d on the basis of life intervention;(3)the amlodipine group(92 cases) was added with amlodipine 5 mg/d on the basis of life intervention. The flow-mediated dilatation(FMD) in brachial artery was used for evaluating the vascular endothelial function and the carotid intima-media thickness(IMT) for evaluating the degree of carotid artery atherosclerosis. The 2-year fol-low up was conducted at regular intervals. The changes of SBP,DBP,FMD,IMT,hypersensitive C-reactive protein (hs-CRP) and biochemical indexes were observed. Results After the 2-year intervention,the body mass index and hs-CRP in each group were decreased compared with before intervention,the difference was statistically significant(P0.05);FMD,SBP and DBP after intervention in each group were improved compared with before intervention,moreover the improvement degree in the candesartan group and amlodipine group was more than that in the life intervention group, the difference was statistically significant(P0.05);after 2-year intervention,IMT in each group was declined,but there was no statistical difference compared with before intervention (P>0.05). Conclusion On the basis of improving lifestyle,adding small dose of anti-hypertensive drugs can improve the

  2. Dual delivery of vascular endothelial growth factor and hepatocyte growth factor coacervate displays strong angiogenic effects.

    Science.gov (United States)

    Awada, Hassan K; Johnson, Noah R; Wang, Yadong

    2014-05-01

    Controlled delivery of multiple growth factors (GFs) holds great potential for the clinical treatment of ischemic diseases and might be more therapeutically effective to reestablish vasculature than the provision of a single GF. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are two potent angiogenic factors. However, due to rapid degradation and dilution in the body, their clinical potential will rely on an effective mode of delivery. A coacervate, composed of heparin and a biodegradable polycation, which protects GFs from proteolysis and potentiates their bioactivities, is developed. Here, the coacervate incorporates VEGF and HGF and sustains their release for at least three weeks. Their strong angiogenic effects on endothelial cell proliferation and tube formation in vitro are confirmed. Furthermore, it is demonstrated that coacervate-based delivery of these factors has stronger effects than free application of both factors and to coacervate delivery of each GF separately.

  3. ABOUT NOXA, VASCULAR RISK FACTORS, ENDOTHELIAL DYSFUNCTION, AND CONSECUTIVE VASCULOPATHY BUT A LITTLE DIFFERENTLY: HOLISTIC APPROACH OF THE PROBLEM (PRELIMINARY COMMUNICATION

    Directory of Open Access Journals (Sweden)

    Tamás Fischer

    2013-02-01

    /disturbing influences/noxious effects!, respectively the proportion is greater: it exposes the cellular constituents to internally generated oxidative attack. As a part of the host defense response, any kind of noxa including the risk factors endangering steadiness of homeostasis start/trigger off an defensive chain founded on increased ROS formation (permanently existing/repeating noxa→persistent/lasting increased ROS formation→oxidative stress→endothelial activation, endothelial dysfunction, respectively → |chronic| vascular injury. The difference between normal host defense and detrimental cellular activation may well be a consequence of the nature, extent, duration, and combination of the proinflammatory stimuli: a profound but transient reduction of endothelium-dependent dilatation may be adaptive and not necessarily pro-vasculopathoghenic, but could become so if other adverse environmental conditions are also present, or if the foreign/unaccustomed stimuli become stable/permanent/lasting, respectivly.Wall of blood vessels may be triggered by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic, and genetic influences-impacts-stimuli (noxa, against which protracted response, the so-called host defense response may develop, and in consequence of this, vascular damage pathological consecutive changes ending in vascular injury , ultimately, may develop. Recovery of endothelial function occurs in response to strategies known to reduce cardiovascular events: this adds support to the concept that restoration of endothelial function can restabilize the chronic vascular disease process. (I Non-medicinal influencing of vascular endothelial dysfunction (ED, the lifestyle modifications, respestively, is of indispensable importance. Lifestyle risk factors modifications, including (1 smoking, (2 dietary habits (prescribing flavonoids, omega-3 long-chain polyunsaturated fatty acids (LCPUFAs, management of dietary GI, (3 modification of physical

  4. Effects of Azardirachta indica on Vascular Endothelial Growth Factor and Cytokines in Diabetic Deep Wound.

    Science.gov (United States)

    Gautam, Manish Kumar; Gangwar, Mayank; Singh, Surya Kumar; Goel, Raj Kumar

    2015-06-01

    A chronic, unhealed diabetic wound is one of the severe complications of diabetes mellitus. Azadirachta indica has been reported to have antidiabetic and antiapoptotic properties. The present work incorporates the healing potential of 50 % ethanol A. indica leaves extract against deep surgical wounds in streptozotocin-induced mild diabetic rats. A. indica leaves extract (500 mg/kg) was administered orally, once daily for ten days. Serum glucose, cholesterol, and triglycerides as well as body weight, food, and water intake, and tissue antioxidants (catalase, superoxide dismutase and reduced glutathione), free radicals (lipid peroxidation and nitric oxide), myeloperoxidase, total collagens (hydroxyproline, hexuronic acid and hexosamine), protein, vascular endothelial growth factor, and cytokines (tumor necrotic factor-α and interleukin-1β) were estimated. Histology was done for connective tissue formation and inflammatory and healing in deep granulation tissue after A. indica leaves extract treatment. Diabetic rats showed an increase in serum glucose, cholesterol, and triglycerides levels, food and water intake, and granular tissue free radicals, myeloperoxidase, and cytokines, but a decrease in body weight, total collagen, and vascular endothelial growth factor levels. A. indica leaves extract reversed the increased serum glucose, cholesterol, and triglycerides, food and water intake, and tissue free radicals, myeloperoxidase and, cytokines, but increased body weight, tissue antioxidants, total collagen, and vascular endothelial growth factor contents. The results thus indicated an improvement in wound healing by A. indica leaves extract in diabetic rats through enhanced angiogenesis mediated through the inhibition of hyperglycemia, oxidative stress, and down- and upregulation of inflammatory mediators and growth factor expression.

  5. Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yu-hua; WEI Wei; XU Hao; WANG Yan-yan; WU Wen-xi

    2007-01-01

    Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells.Methods Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA.The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells.Results Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.Conclusion This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial growth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT signaling pathways.

  6. Activation of adenosine A2A receptors by polydeoxyribonucleotide increases vascular endothelial growth factor and protects against testicular damage induced by experimental varicocele in rats.

    Science.gov (United States)

    Minutoli, Letteria; Arena, Salvatore; Bonvissuto, Giulio; Bitto, Alessandra; Polito, Francesca; Irrera, Natasha; Arena, Francesco; Fragalà, Eugenia; Romeo, Carmelo; Nicotina, Piero Antonio; Fazzari, Carmine; Marini, Herbert; Implatini, Alessandra; Grimaldi, Silvia; Cantone, Noemi; Di Benedetto, Vincenzo; Squadrito, Francesco; Altavilla, Domenica; Morgia, Giuseppe

    2011-03-15

    In rat experimental varicocele, polydeoxyribonucleotide (PDRN) induces vascular endothelial growth factor (VEGF) production, thereby enhancing testicular function. This may point to a new therapeutic approach in human varicocele.

  7. Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells

    Science.gov (United States)

    Trau, Heidi A.; Brännström, Mats; Curry, Thomas E.; Duffy, Diane M.

    2016-01-01

    STUDY QUESTION Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation? SUMMARY ANSWER PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis. WHAT IS KNOWN ALREADY Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis. STUDY DESIGN, SIZE, DURATION Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30–45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18–31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs). PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix. MAIN RESULTS AND THE ROLE OF CHANCE Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18–34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but

  8. Expression of vascular endothelial growth factor in serum of umbilical blood from the newborns of women with severe pre-eclampsia%血管内皮生长因子在重度子癎痫前期产妇新生儿脐血中的表达

    Institute of Scientific and Technical Information of China (English)

    王萍; 张巍; 陈素娟

    2009-01-01

    Objective To study the expression and significance of vascular endothelial growth factor(VEGF) in serum of umbilical blood from the newborns of women with severe pre-eclampsia.Methods Radioimmunoassay was used to measure the serum VEGF of umbilical blood from 26 newborns of women with severe pre-eclampsia (severe pre-eclmpsia group) and 30 newborns of normal pregnancy women (control group). According to birth weight-gestational age relation,severe pre-eclampsia group included 15 newborns small for gestational age (SGA group) and 11 newborns appropriate for gestational age (AGA group).Results (1)The VEGF level of umbilical vein blood and umbilical artery blood in severe pre-eclmpsia group was significantly higher than that in control group respectively(t = 2.16, P < 0.05;t = 4.82, P < 0.01). (2) In control group and severe pre-eclampsia group, the VEGF level in umbilical artery blood was significantly higher than that in umbilical vein blood (control group: t = 2.24, P < 0.05;severe pre-eclampsia group: t = 3.00, P < 0.01). (3)In both control group and severe pre-eclampsia group, there was no significant correlation respectively between VEGF levels in umbilical vein blood or umbilical artery blood and newborns' gestational age or birth weight. (4)VEGF level of umbilical artery blood in SGA group was significantly higher than that in AGA group as well as in control group(t = 3.22, P < 0.01 ;t = 6.80, P < 0.01). Conclusions The serum VEGF level of umbilical vein blood and umbilical artery blood from the newborns of women with severe pre-eclampsia was significantly higher than that of normal pregnancy women respectively. The VEGF level of umbilical artery blood can reflect the severity degree of the damage of hypertensive disorder complicating pregnancy to their newborns to some degree.%目的 探讨血管内皮生长因子(VEGF)在重度子癎前期产妇分娩的新生儿脐静脉血、脐动脉血中的表达及其意义.方法 采用放射免疫分析法检测26

  9. Role of vascular endothelial growth factor in reconstructive surgery after surgical excision of malignant tumor

    Institute of Scientific and Technical Information of China (English)

    麻鹏; 刘春丽

    2008-01-01

    As a key mediator of normal physiological angiogenesis,vascular endothelial growth factor(VEGF)has been regarded as an emancipator to plastic surgeon,and yet a misfortune to oncology surgeon,due to its sin-gular biological effect.Therefore in some clinical cases,especially for some malignant tumor patients having en-dured radical surgery and being craving for a reconstructive surgery,VEGF plays a role full of paradoxes.To make a clinical balance,we should find a point to inhibit tumor cell from utilizing VEGF and make a permission to normal tissues to employ it.

  10. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

    Directory of Open Access Journals (Sweden)

    McLoughlin Paul

    2011-01-01

    Full Text Available Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2 or hypoxia (10% O2 for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA, VEGFB, placenta growth factor (PlGF, VEGF receptor 1 (VEGFR1 and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or

  11. Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway.

    Science.gov (United States)

    Desar, Ingrid M E; Thijs, Annemarie M J; Mulder, Sasja F; Tack, Cees J J; van Herpen, Carla M L; van der Graaf, Winette T A

    2012-02-01

    Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

  12. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

    LENUS (Irish Health Repository)

    Sands, Michelle

    2011-01-25

    Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF) family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF) and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2) or hypoxia (10% O2) for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA), VEGFB, placenta growth factor (PlGF), VEGF receptor 1 (VEGFR1) and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or potentiate the

  13. Glutamate enhances the expression of vascular endothelial growth factor in cultured SD rat astrocytes

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups:control group (C),glutamate group (G),QA group (Q),DCG-IV group (D),L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air,5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes,respect...

  14. Vascular Endothelial Growth Factor Levels in Dobrava/Belgrade Virus Infections

    Directory of Open Access Journals (Sweden)

    Katerina Tsergouli

    2013-12-01

    Full Text Available The levels of vascular endothelial growth factor-A (VEGF were estimated in 102 serum samples from 63 hospitalized Greek patients with hemorrhagic fever with renal syndrome (HFRS caused by Dobrava/Belgrade virus. Significantly higher VEGF levels were seen in the severe when compared with non-severe cases (mean values 851.96 pg/mL and 326.75 pg/mL, respectively; p = 0.003, while a significant difference was observed among groups based on the day after the onset of illness. In both severe and non-severe cases, VEGF peaked in the second week of illness; however, elevation of VEGF in the severe cases started later and remained high until convalescence, suggesting that the role of VEGF was associated with repair of vascular damage rather than with increased permeability.

  15. Vascular endothelial growth factor levels in dobrava/belgrade virus infections.

    Science.gov (United States)

    Tsergouli, Katerina; Papa, Anna

    2013-12-10

    The levels of vascular endothelial growth factor-A (VEGF) were estimated in 102 serum samples from 63 hospitalized Greek patients with hemorrhagic fever with renal syndrome (HFRS) caused by Dobrava/Belgrade virus. Significantly higher VEGF levels were seen in the severe when compared with non-severe cases (mean values 851.96 pg/mL and 326.75 pg/mL, respectively; p = 0.003), while a significant difference was observed among groups based on the day after the onset of illness. In both severe and non-severe cases, VEGF peaked in the second week of illness; however, elevation of VEGF in the severe cases started later and remained high until convalescence, suggesting that the role of VEGF was associated with repair of vascular damage rather than with increased permeability.

  16. Protection against vascular endothelial dysfunction by polyphenols in sea buckthorn berries in rats with hyperlipidemia.

    Science.gov (United States)

    Yang, Fang; Suo, Yourui; Chen, Dongli; Tong, Li

    2016-07-19

    Chronic hyperlipemia increases the incidence of vascular endothelial dysfunction and can even induce cardiovascular disease. Sea buckthorn contains a host of bioactives such as flavonoids and polyphenols that can prevent the development of cardiovascular disease. The current study isolated active ingredients, polyphenols, from sea buckthorn berries (SVP) and orally administered SVP at a dose of 7-28 mg/kg. This treatment significantly reduced serum lipids, it enhanced the activity of antioxidant enzymes, and it decreased the level of serum TNF-α and IL-6. SVP also alleviate vascular impairment by decreasing the expression of eNOS, ICAM-1, and LOX-1 mRNA and proteins in aortas of rats with hyperlipidemia. Based on these findings, SVP has antioxidant action and it protects endothelium.

  17. Effect of Xuebijing Injection on Vascular Endothelial Growth Factor in Peripheral Blood in Patients with Severe Pulmonary Contusion%血必净注射液对严重肺挫伤患者外周血中血管内皮生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    韩冬; 黄伟

    2014-01-01

    Objective To observe the effect of Xuebijing injection on vascular endothelial growth factor ( VEGF) in peripheral blood in patients with severe pulmonary contusion. Methods A total of 65 patients with severe pulmonary contusion in the Third People's Hospital of Wuxi during September 2011 and January 2014 were randomly di-vided into observation group ( n=31 ) and control group ( n=34 ) . The control group received routine comprehensive treatment. Based on the routine comprehensive treatment, the observation group was treated with 50 ml Xuebijing injec-tion diluted with 100 ml of physiological saline twice a day, and one course of treatment was 7 d. The serum VEGF levels were detected on 1st d, 3rd d, 5th d and 7th d after injuries by enzyme linked immunosorbent assay (ELISA)respectively, and related clinical indexes in the two groups were compared. Results The serum VEGF level changed dynamically in observation group, and it decreased gradually on 1st d after injury. Compared with those in control group, the differences of VEGF levels on 3rd d, 5th d and 7th d after injuries were statistically significant (P  观察组血清VEGF含量呈动态变化,伤后第1天开始逐渐下降,与对照组相比,在第3、5、7天的差异均有统计学意义(P<0.01)。观察组全身炎症反应综合征(SIRS)发生率、机械通气率和病死率均显著低于对照组(P<0.05),机械通气时间、住院时间也均显著短于对照组(P<0.05)。结论血必净注射液能够降低严重肺挫伤患者外周血中VEGF水平,从而减轻VEGF高表达所带来的肺损伤,明显改善预后,值得临床推广应用。

  18. Analysis of p53 and vascular endothelial growth factor expression in human gallbladder carcinoma for the determination of tumor vascularity

    Institute of Scientific and Technical Information of China (English)

    Yu Tian; Ren-Yu Ding; Ying-Hui Zhi; Ren-Xuan Guo; Shuo-Dong Wu

    2006-01-01

    AIM: To examine the expression of p53 and vascular endothelial growth factor (VEGF) as well as microvessel count (MVC) and to investigate the role of VEGF as an angiogenic marker and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma.METHODS: Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, and factor Ⅷ-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage,differentiation grade, MVC, and lymph node metastasis.RESULTS: Positive p53 protein and VEGF expressions were found in 61.2% and 63.3% of tumors, respectively.p53 and VEGF staining status was identical in 55.1%of tumors. The Nevin staging of p53- or VEGF-positive tumors was significantly later than that of negative tumors. The MVC in p53- or VEGF-positive tumors was significantly higher than that in negative tumors,and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups.CONCLUSION: Our findings suggest that p53-VEGF pathway can regulate tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the tumor vascularity of gallbladder cancer.

  19. C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression

    Directory of Open Access Journals (Sweden)

    Luque Ana

    2008-09-01

    Full Text Available Abstract Background Formation of haemorrhagic neovessels in the intima of developing atherosclerotic plaques is thought to significantly contribute to plaque instability resulting in thrombosis. C-reactive protein (CRP is an acute phase reactant whose expression in the vascular wall, in particular, in reactive plaque regions, and circulating levels increase in patients at high risk of cardiovascular events. Although CRP is known to induce a pro-inflammatory phenotype in endothelial cells (EC a direct role on modulation of angiogenesis has not been established. Results Here, we show that CRP is a powerful inducer of angiogenesis in bovine aortic EC (BAEC and human coronary artery EC (HCAEC. CRP, at concentrations corresponding to moderate/high risk (1–5 μg/ml, induced a significant increase in proliferation, migration and tube-like structure formation in vitro and stimulated blood vessel formation in the chick chorioallantoic membrane assay (CAM. CRP treated with detoxi-gel columns retained such effects. Western blotting showed that CRP increased activation of early response kinase-1/2 (ERK1/2, a key protein involved in EC mitogenesis. Furthermore, using TaqMan Low-density Arrays we identified key pro-angiogenic genes induced by CRP among them were vascular endothelial cell growth factor receptor-2 (VEGFR2/KDR, platelet-derived growth factor (PDGF-BB, notch family transcription factors (Notch1 and Notch3, cysteine-rich angiogenic inducer 61 (CYR61/CCN1 and inhibitor of DNA binding/differentiation-1 (ID1. Conclusion This data suggests a role for CRP in direct stimulation of angiogenesis and therefore may be a mediator of neovessel formation in the intima of vulnerable plaques.

  20. The defensive effect of benfotiamine in sodium arsenite-induced experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Verma, Sanjali; Reddy, Krishna; Balakumar, Pitchai

    2010-10-01

    The present study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Sodium arsenite (1.5 mg(-1) kg(-1) day(-1) i.p., 2 weeks) was administered in rats to produce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating the serum and aortic concentrations of nitrite/nitrate. Further, the integrity of vascular endothelium in thoracic aorta was assessed by scanning electron microscopy. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of sodium arsenite markedly produced VED by attenuating acetylcholine-induced endothelium-dependent relaxation, decreasing serum and aortic concentrations of nitrite/nitrate, and impairing the integrity of vascular endothelium. Further, sodium arsenite produced oxidative stress by increasing serum TBARS and aortic superoxide generation. The treatment with benfotiamine (25, 50, and 100 mg(-1) kg(-1) day(-1) p.o.) or atorvastatin (30 mg(-1) kg(-1) day(-1) p.o., a standard agent) prevented sodium arsenite-induced VED and oxidative stress. However, the beneficial effects of benfotiamine in preventing the sodium arsenite-induced VED were attenuated by co-administration with N-omega-nitro-L: -arginine methyl ester (L: -NAME) (25 mg(-1) kg(-1) day(-1), i.p.), an inhibitor of NOS. Thus, it may be concluded that benfotiamine reduces oxidative stress and activates endothelial nitric oxide synthase to enhance the generation and bioavailability of NO and subsequently improves the integrity of vascular endothelium to prevent sodium arsenite-induced experimental VED.

  1. Endothelial and non-endothelial coronary blood flow reserve and left ventricular dysfunction in systemic hypertension

    Directory of Open Access Journals (Sweden)

    Aloísio Marchi Rocha

    2009-04-01

    Full Text Available OBJECTIVES: We evaluated the impairment of endothelium-dependent and endothelium-independent coronary blood flow reserve after administration of intracoronary acetylcholine and adenosine, and its association with hypertensive cardiac disease. INTRODUCTION: Coronary blood flow reserve reduction has been proposed as a mechanism for the progression of compensated left ventricular hypertrophy to ventricular dysfunction. METHODS: Eighteen hypertensive patients with normal epicardial coronary arteries on angiography were divided into two groups according to left ventricular fractional shortening (FS. Group 1 (FS >0.25: n=8, FS=0.29 ± 0.03; Group 2 (FS <0.25: n=10, FS= 0.17 ± 0.03. RESULTS: Baseline coronary blood flow was similar in both groups (Group 1: 80.15 ± 26.41 mL/min, Group 2: 100.09 ± 21.51 mL/min, p=NS. In response to adenosine, coronary blood flow increased to 265.1 ± 100.2 mL/min in Group 1 and to 300.8 ± 113.6 mL/min (p <0.05 in Group 2. Endothelium-independent coronary blood flow reserve was similar in both groups (Group 1: 3.31 ± 0.68 and Group 2: 2.97 ± 0.80, p=NS. In response to acetylcholine, coronary blood flow increased to 156.08 ± 36.79 mL/min in Group 1 and to 177.8 ± 83.6 mL/min in Group 2 (p <0.05. Endothelium-dependent coronary blood flow reserve was similar in the two groups (Group 1: 2.08 ± 0.74 and group Group 2: 1.76 ± 0.61, p=NS. Peak acetylcholine/peak adenosine coronary blood flow response (Group 1: 0.65 ± 0.27 and Group 2: 0.60 ± 0.17 and minimal coronary vascular resistance (Group 1: 0.48 ± 0.21 mmHg/mL/min and Group 2: 0.34 ± 0.12 mmHg/mL/min were similar in both groups (p= NS. Casual diastolic blood pressure and end-systolic left ventricular stress were independently associated with FS. CONCLUSIONS: In our hypertensive patients, endothelium-dependent and endothelium-independent coronary blood flow reserve vasodilator administrations had similar effects in patients with either normal or decreased left

  2. Isoform of Vascular Endothelial Cell Growth Inhibitor (VEGI72-251) Increases Interleukin-2 Production by Activation of T Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Jing-Juan YAO; Min ZHANG; Xiao-Hui MIAO; Ping ZHAO; Shi-Ying ZHU; Hui DING; Zhong-Tian QI

    2006-01-01

    The objective of this study is to investigate the characteristics of the recombinant variant of human vascular endothelial cell growth inhibitor, VEGI72-251, and compare its biological activities with that of its prototype VEGI24-174. The recombinant plasmid containing the variant VEGI72-251 gene was constructed and expressed in Escherichia coli. The effects of the expressed VEGI72-251 on cell proliferations were checked in the human umbilical vein endothelial cell line and certain tumor cell lines (ECV304 and B 16). The inhibition of VEGI72-251 on angiogenesis was detected in the chorioallantoic membrane of chick embryos. In comparison with VEGI24-174, the recombinant human VEGI72-251 seems to have no effect on the proliferation of endothelial cells and the angiogenesis of the chorioallantoic membrane in vitro. An enzyme-linked immunosorbent assaybased method was used for the measurement of interleukin-2 (IL-2) production by peripheral blood monocytes (PBMCs) treated with VEGI72-251. PBMCs were pretreated with VEGI72-251 (1.25-12.50 μg/ml) for 24 h in vitro, and the IL-2 concentration in PBMC medium was increased from 354 pg/ml to 1256 pg/ml. It can be concluded that VEGI72-251 is able to increase the level of human IL-2 production by the activation of T lymphocytes. Differing from VEGI24-174 on anti-angiogenesis, VEGI72-251 may serve as an anti-cancer factor through its activation of T lymphocytes.

  3. Increased expression of the sonic hedgehog and vascular endothelial growth factor with co-localization in varicocele veins.

    Science.gov (United States)

    Wang, Shih-Ho; Yang, Wen-Kai; Lee, Jane-Dar

    2017-03-01

    Objectives Varicocele is characterized by dilatation and tortuosity of the internal spermatic vein. Sonic hedgehog plays an important role in angiogenesis and vascular remodeling under hypoxic stress. We studied the relationship and distribution of SHH and vascular endothelial growth factor in internal spermatic vein in patients diagnosed with varicocele. Methods Specimens of 1 cm were taken from the internal spermatic vein during left varicocele repair (N = 20). The control samples of ISV were obtained from eight male patients who underwent left inguinal herniorrhaphy. We analyzed the sonic hedgehog and vascular endothelial growth factor expression and distribution by immunoblotting, immunohistochemistry, immunofluorescent staining, and confocal laser scanning microscopy. The data were analyzed using the Student's t test. Results Immunoblotting showed higher expression of sonic hedgehog and vascular endothelial growth factor proteins in varicocele veins than in the control group ( P sonic hedgehog and vascular endothelial growth factor with co-localization in varicocele veins which imply that the reducing hypoxia or using sonic hedgehog antagonists may be helpful for this vascular disease.

  4. F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

    Science.gov (United States)

    Heemskerk, Niels; Schimmel, Lilian; Oort, Chantal; van Rijssel, Jos; Yin, Taofei; Ma, Bin; van Unen, Jakobus; Pitter, Bettina; Huveneers, Stephan; Goedhart, Joachim; Wu, Yi; Montanez, Eloi; Woodfin, Abigail; van Buul, Jaap D

    2016-01-27

    During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during the physical movement of neutrophils through the endothelial layer. Local RhoA activation initiates the formation of contractile F-actin structures that surround emigrating neutrophils. These structures that surround neutrophil-induced endothelial pores prevent plasma leakage through actomyosin-based pore confinement. Mechanistically, we found that the initiation of RhoA activity involves ICAM-1 and the Rho GEFs Ect2 and LARG. In addition, regulation of actomyosin-based endothelial pore confinement involves ROCK2b, but not ROCK1. Thus, endothelial cells assemble RhoA-controlled contractile F-actin structures around endothelial pores that prevent vascular leakage during leukocyte extravasation.

  5. Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development.

    Science.gov (United States)

    Magnusson, Peetra; Rolny, Charlotte; Jakobsson, Lars; Wikner, Charlotte; Wu, Yan; Hicklin, Daniel J; Claesson-Welsh, Lena

    2004-03-15

    We have employed embryoid bodies derived from murine embryonal stem cells to study effects on vascular development induced by fibroblast growth factor (FGF)-2 and FGF receptor-1, in comparison to the established angiogenic factor vascular endothelial growth factor (VEGF)-A and its receptor VEGF receptor-2. Exogenous FGF-2 promoted formation of morphologically distinct, long slender vessels in the embryoid bodies, whereas VEGF-A-treated bodies displayed a compact plexus of capillaries. FGF-2 stimulation of embryonal stem cells under conditions where VEGF-A/VEGFR-2 function was blocked, led to formation of endothelial cell clusters, which failed to develop into vessels. FGFR-1(-/-) embryoid bodies responded to VEGF-A by establishment of the characteristic vascular plexus, but FGF-2 had no effect on vascular development in the absence of FGFR-1. The FGFR-1(-/-) embryoid bodies displayed considerably increased basal level of vessel formation, detected by immunohistochemical staining for platelet-endothelial cell adhesion molecule (PECAM)/CD31. This basal vascularization was blocked by neutralizing antibodies against VEGFR-2 or VEGF-A and biochemical analyses indicated changes in regulation of VEGFR-2 in the absence of FGFR-1 expression. We conclude that VEGF-A/VEGFR-2-dependent vessel formation occurs in the absence of FGF-2/FGFR-1, which, however, serve to modulate vascular development.

  6. Vascular endothelial growth factor (VEGF), produced by feline infectious peritonitis (FIP) virus-infected monocytes and macrophages, induces vascular permeability and effusion in cats with FIP.

    Science.gov (United States)

    Takano, Tomomi; Ohyama, Taku; Kokumoto, Aiko; Satoh, Ryoichi; Hohdatsu, Tsutomu

    2011-06-01

    Feline infectious peritonitis virus (FIPV) causes a fatal disease called FIP in Felidae. The effusion in body cavity is commonly associated with FIP. However, the exact mechanism of accumulation of effusion remains unclear. We investigated vascular endothelial growth factor (VEGF) to examine the relationship between VEGF levels and the amounts of effusion in cats with FIP. Furthermore, we examined VEGF production in FIPV-infected monocytes/macrophages, and we used feline vascular endothelial cells to examine vascular permeability induced by the culture supernatant of FIPV-infected macrophages. In cats with FIP, the production of effusion was related with increasing plasma VEGF levels. In FIPV-infected monocytes/macrophages, the production of VEGF was associated with proliferation of virus. Furthermore, the culture supernatant of FIPV-infected macrophages induced hyperpermeability of feline vascular endothelial cells. It was suggested that vascular permeability factors, including VEGF, produced by FIPV-infected monocytes/macrophages might increase the vascular permeability and the amounts of effusion in cats with FIP.

  7. Vascular Endothelial-Targeted Therapy Combined with Cytotoxic Chemotherapy Induces Inflammatory Intratumoral Infiltrates and Inhibits Tumor Relapses after Surgery

    Directory of Open Access Journals (Sweden)

    Brendan F. Judy

    2012-04-01

    Full Text Available Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS, cisplatin (cis, or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02. Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.

  8. Point-of-care seeding of nitinol stents with blood-derived endothelial cells.

    Science.gov (United States)

    Jantzen, Alexandra E; Noviani, Maria; Mills, James S; Baker, Katherine M; Lin, Fu-Hsiung; Truskey, George A; Achneck, Hardean E

    2016-11-01

    Nitinol-based vascular devices, for example, peripheral and intracranial stents, are limited by thrombosis and restenosis. To ameliorate these complications, we developed a technology to promote vessel healing by rapidly seeding (QuickSeeding) autologous blood-derived endothelial cells (ECs) onto modified self-expanding nitinol stent delivery systems immediately before implantation. Several thousand micropores were laser-drilled into a delivery system sheath surrounding a commercial nitinol stent to allow for exit of an infused cell suspension. As suspension medium flowed outward through the micropores, ECs flowed through the delivery system attaching to the stent surface. The QuickSeeded ECs adhered to and spread on the stent surface following 24-h in vitro culture under static or flow conditions. Further, QuickSeeded ECs on stents that were deployed into porcine carotid arteries spread to endothelialize stent struts within 48 h (n = 4). The QuickSeeded stent struts produced significantly more nitric oxide in ex vivo flow circuits after 24 h, as compared to static conditions (n = 5). In conclusion, ECs QuickSeeded onto commercial nitinol stents within minutes of implantation spread to form a functional layer in vitro and in vivo, providing proof of concept that the novel QuickSeeding method with modified delivery systems can be used to seed functional autologous endothelium at the point of care. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1658-1665, 2016.

  9. Thermal reactions of blood vessels in vascular stroke and heatstroke.

    Science.gov (United States)

    Thulesius, Olav

    2006-01-01

    Research on the pathophysiology and treatment of brain damage with special focus on thermal vascular responses is the subject of this minireview. Interruption of cerebral blood supply by vascular obstruction, temporary cardiac arrest or hyperthermia causes a sudden attack of vascular stroke or heatstroke with serious consequences. It may not induce immediate cell death, but can precipitate a complex biochemical cascade leading to a delayed neuronal loss. When testing thermal vasomotor responses by stepwise cooling of isolated carotid arteries, a temperature-proportional dilatation was observed while heating induced the opposite response: a marked vasoconstriction. General hyperthermia with an increased oxygen demand combined with a reduction of blood supply therefore is a serious consequence. At the cellular level an important mechanism involving hyperthermia is the temperature-dependent regulation of K(+) channel tone of vascular smooth muscle. Further, their inhibition through temperature elevation causes vasoconstriction. In heatstroke, which can induce platelet aggregation and the release of the vasoconstrictor serotonin, arterial cooling attenuates this response. General hypothermia is induced to prevent or attenuate neurological damage in stroke. The procedure is not without serious side effects. Therefore, rapid institution of selective brain cooling has been considered in adults and in infants with postpartum encephalopathy.

  10. TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Bruneau, Sarah; Datta, Dipak; Flaxenburg, Jesse A.; Pal, Soumitro [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States); Briscoe, David M., E-mail: david.briscoe@childrens.harvard.edu [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States)

    2012-03-02

    Highlights: Black-Right-Pointing-Pointer TNF-receptor associated factors (TRAFs) function in the angiogenesis response. Black-Right-Pointing-Pointer TRAF6 regulates basal and inducible expression of VEGF in endothelial cells (EC). Black-Right-Pointing-Pointer TRAF6 is an endogenous inhibitor of EC proliferation and migration in EC. Black-Right-Pointing-Pointer TRAF6 inhibits VEGF expression in part via its ability to regulate Src signaling. -- Abstract: TNF-family molecules induce the expression Vascular Endothelial Growth Factor (VEGF) in endothelial cells (EC) and elicit signaling responses that result in angiogenesis. However, the role of TNF-receptor associated factors (TRAFs) as upstream regulators of VEGF expression or as mediators of angiogenesis is not known. In this study, HUVEC were cotransfected with a full-length VEGF promoter-luciferase construct and siRNAs to TRAF 1, -2, -3, -5, -6, and promoter activity was measured. Paradoxically, rather than inhibiting VEGF expression, we found that knockdown of TRAF6 resulted in a 4-6-fold increase in basal VEGF promoter activity compared to control siRNA-transfected EC (P < 0.0001). In addition, knockdown of TRAF 1, -2, -3 or -5 resulted in a slight increase or no change in VEGF promoter activation. Using [{sup 3}H]thymidine incorporation assays as well as the in vitro wound healing assay, we also found that basal rates of EC proliferation and migration were increased following TRAF6 knockdown; and this response was inhibited by the addition of a blocking anti-VEGF antibody into cell cultures. Using a limited protein array to gain insight into TRAF6-dependent intermediary signaling responses, we observed that TRAF6 knockdown resulted in an increase in the activity of Src family kinases. In addition, we found that treatment with AZD-0530, a pharmacological Src inhibitor, reduced the regulatory effect of TRAF6 knockdown on VEGF promoter activity. Collectively, these findings define a novel pro-angiogenic signaling

  11. Small interference RNA targeting vascular endothelial growth factor gene effectively attenuates retinal neovascularization in mice model

    Institute of Scientific and Technical Information of China (English)

    KONG Yi-chun; SUN Bei; ZHAO Kan-xing; HAN Mei; WANG Yu-chuan

    2013-01-01

    Background The mechanism of retinal neovascularization is not understood completely.Many growth factors are involved in the process of retinal neovascularization,such as vascular endothelial growth factor (VEGF) and pigment epithelium-deprived factor (PEDF),which are the representatives of angiogenic and antiangiogenic molecules respectively.Oxygen induced retinopathy (OIR) is a useful model to investigate retinal neovascularization.The present study was conducted to investigate the feasibility of small interference RNA (siRNA) targeting VEGF gene in attenuating oxygen induced retinopathy (OIR) by regulating VEGF to PEDF ratio (VEGF/PEDF).Methods In vitro,cultured EOMA cells were transfected with VEGF-siRNA (psi-HITM/EGFPNEGF siRNA) and LipofectamineTM 2000 for 24,48,and 72 hours,respectively.Expression of VEGF mRNA was evaluated by real time polymerase chain reaction (PCR) and the level of VEGF protein was analyzed by Western blotting.In vivo,OIR model mice were established,the mice (C57BL/6J) received an intra-vitreal injection of 1 μl of mixture of psi-HITM/EGFPNEGF siRNA and Lipofectamine 2000.Expressions of retinal VEGF and PEDF protein were measured by Western blotting,retinal neovascularization was observed by fluorescein angiography,and quantified.Results In vitro psi-HITM/EGFP/VEGF siRNA treatment significantly reduced VEGF mRNA and protein expression.In vivo,with decreased VEGF and VEGF-PEDF ratio,significant attenuation of neovascular tufts,avascular regions,tortuous,and dilated blood vessels were observed in the interfered animals.Conclusions VEGF plays an important role in OIR,and the transfection of VEGF-siRNA can effectively downregulate VEGF expression in vivo,accompanied by the downregulation of VEGF-PEDF ratio,and simultaneous attenuation of retinal neovascularization was also observed.These findings suggest that VEGF/PEDF may serve as a potential target in the treatment of retinal neovascularization and RNA interference targeting VEGF expression

  12. Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells.METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy.SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry.RESULTS: The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls.CONCLUSION: Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.

  13. PRIMING EFFECT OF HOMOCYSTEINE ON INDUCIBLE VASCULAR CELL ADHESION MOLECULE-1 EXPRESSION IN ENDOTHELIAL CELLS

    Science.gov (United States)

    Séguin, Chantal; Abid, Md. Ruhul; Spokes, Katherine C.; Schoots, Ivo G; Brkovic, Alexandre; Sirois, Martin G.; Aird, William C.

    2017-01-01

    Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, as well as for arterial and venous thrombosis. However, the mechanisms through which elevated circulating levels of homocysteine cause vascular injury and promote thrombosis remain unclear. Here, we tested the hypothesis that homocysteine (Hcy) sensitizes endothelial cells to the effect of inflammatory mediators. Human umbilical vein endothelial cells (HUVEC) were incubated with Hcy 1.0 mM for varying time points, and then treated in the absence or presence of 1.5 U/ml thrombin or 10 ng/ml lipopolysaccharide (LPS). Hcy alone had no effect on the expression of vascular cell adhesion molecule (VCAM)-1. However, Hcy enhanced thrombin- and LPS-mediated induction of VCAM-1 mRNA and protein levels. Consistent with these results, pretreatment of HUVEC with Hcy resulted in a two-fold increase in LSP-mediated induction of leukocyte adhesion. The latter effect was significantly inhibited by anti-VCAM-1 antibodies. Together, these findings suggest that Hcy sensitizes HUVEC to the effect of inflammatory mediators thrombin and LPS, at least in part through VCAM-1 expression and function. PMID:18406566

  14. Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling.

    Science.gov (United States)

    Huang, Shiu-Wen; Lien, Jin-Cherng; Kuo, Sheng-Chu; Huang, Tur-Fu

    2012-05-01

    Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.

  15. Vascular endothelial growth factor promotes peripheral nerve regeneration after sciatic nerve transection in rat

    Directory of Open Access Journals (Sweden)

    Mohammadi Rahim

    2013-12-01

    Full Text Available 【Abstract】Objective: To evaluate the local effect of vascular endothelial growth factor (VEGF on transected sciatic nerve regeneration. Methods: Sixty male white Wistar rats were divided into four experimental groups randomly (n=15. In transected group the left sciatic nerve was transected and the stump was fixed to adjacent muscle. In treatment group the defect was bridged using a silicone graft filled with 10 µL VEGF. In silicone group the graft was filled with phosphate-buffered saline. In sham-operated group the sciatic nerve was ex- posed and manipulated. Each group was subdivided into three subgroups with five animals in each and nerve fibers were studied 4, 8 and 12 weeks after operation. Results: Behavioral test, functional study of sciatic nerve, gastrocnemius muscle mass and morphometric indi- ces confirmed a faster recovery of regenerated axons in VEGF group than in silicone group (P<0.05. In immunohistochemi- cal assessment, reactions to S-100 in VEGF group were more positive than that in silicone group. Conclusion: Local administration of VEGF will im- prove functional recovery and morphometric indices of sci- atic nerve. Key words: Peripheral nerves; Nerve regeneration; Sciatic nerve; Vascular endothelial growth factor

  16. Role of vascular endothelial growth factor and other growth factors in post-stroke recovery

    Directory of Open Access Journals (Sweden)

    Tanu Talwar

    2014-01-01

    Full Text Available Stroke is a major health problem world-wide and its burden has been rising in last few decades. Until now tissue plasminogen activator is only approved treatment for stroke. Angiogenesis plays a vital role for striatal neurogenesis after stroke. Administration of various growth factors in an early post ischemic phase, stimulate both angiogenesis and neurogenesis and lead to improved functional recovery after stroke. However vascular endothelial growth factors (VEGF is the most potent angiogenic factor for neurovascularization and neurogenesis in ischemic injury can be modulated in different ways and thus can be used as therapy in stroke. In response to the ischemic injury VEGF is released by endothelial cells through natural mechanism and leads to angiogenesis and vascularization. This release can also be up regulated by exogenous administration of Mesenchymal stem cells, by various physical therapy regimes and electroacupuncture, which further potentiate the efficacy of VEGF as therapy in post stroke recovery. Recent published literature was searched using PubMed and Google for the article reporting on methods of up regulation of VEGF and therapeutic potential of growth factors in stroke.

  17. Establishment of the model of vascular endothelial cell membrane chromatography and its preliminary application

    Institute of Scientific and Technical Information of China (English)

    LI YiPing; HE LangChong

    2007-01-01

    A model of vascular endothelial cell membrane chromatography was established by using an ECV304 cell membrane stationary phase (ECV304 CMSP) prepared by immobilizing the ECV304 cell membrane onto the surface of silica carrier. The surface and chromatographic characteristics of ECV304 CMSP were studied. The active component from Caulophyllum robustum was screened by using the model of vascular endothelial cell membrane chromatography. The interaction between the active component and membrane receptor was determined by using a replace experiments. The effect of the active component was tested by using tube formation of ECV304 cell. The results indicated that the model of ECV304 cell membrane chromatograph (ECV304 CMC) can stimulate the interaction between drug and receptor in vitro and the retention characteristics of taspine as active component was similar to that of model molecule in the model of ECV304 CMC. And therefore, taspine acted on VEGFR2 and inhibited the tube formation of ECV304 cell induced by VEGF. This model can be used to screen definite active component as a screening model.

  18. Role of 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids in the regulation of vascular function in a model of hypertension and endothelial dysfunction.

    Science.gov (United States)

    Yousif, Mariam H M; Benter, Ibrahim F

    2010-01-01

    The objective of this study was to determine if acute inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis or reduced inactivation of epoxyeicosatrienoic acids (EETs) can correct L-N(G)-nitro-arginine-methyl-ester (L-NAME)-induced abnormal vascular reactivity in the perfused mesenteric bed and the carotid artery of spontaneously hypertensive rats (SHR). Administration of L-NAME in drinking water (80 mg/l) to SHR for 3 weeks resulted in abnormal vascular reactivity to norepinephrine and carbachol in the perfused mesenteric vascular bed and carotid artery, and significantly elevated mean arterial blood pressure (244 +/- 9 mm Hg) as compared to SHR controls drinking regular water (176 +/- 3 mm Hg). In the perfused mesenteric vascular bed, the impaired vascular responsiveness to norepinephrine was corrected by acute treatment with N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016), an inhibitor of 20-HETE formation, but not by 1-cyclohexyl-3-dodecyl urea (CDU), an inhibitor of soluble epoxide hydrolase. Treatment with either HET0016 or CDU did not improve impaired carbachol-induced vasodilation in the perfused mesenteric vascular bed. In the isolated carotid artery, treatment with HET0016 corrected the L-NAME-induced increase in norepinephrine-induced vasoconstriction, whereas only CDU treatment could improve impaired carbachol-induced vasodilation. Results of this study indicate that vascular function in a state of compromised nitric oxide formation is differentially modulated by 20-HETE and EETs, and that treatment with HET0016 or CDU may improve vascular function in a state of high blood pressure and endothelial dysfunction.

  19. Magnetic ferroferric oxide nanoparticles induce vascular endothelial cell dysfunction and inflammation by disturbing autophagy.

    Science.gov (United States)

    Zhang, Lu; Wang, XueQin; Miao, YiMing; Chen, ZhiQiang; Qiang, PengFei; Cui, LiuQing; Jing, Hongjuan; Guo, YuQi

    2016-03-01

    Despite the considerable use of magnetic ferroferric oxide nanoparticles (Fe3O4NPs) worldwide, their safety is still an important topic of debate. In the present study, we detected the toxicity and biological behavior of bare-Fe3O4NPs (B-Fe3O4NPs) on human umbilical vascular endothelial cells (HUVECs). Our results showed that B-Fe3O4NPs did not induce cell death within 24h even at concentrations up to 400 μg/ml. The level of nitric oxide (NO) and the activity of endothelial NO synthase (eNOS) were decreased after exposure to B-Fe3O4NPs, whereas the levels of proinflammatory cytokines were elevated. Importantly, B-Fe3O4NPs increased the accumulation of autophagosomes and LC3-II in HUVECs through both autophagy induction and the blockade of autophagy flux. The levels of Beclin 1 and VPS34, but not phosphorylated mTOR, were increased in the B-Fe3O4NP-treated HUVECs. Suppression of autophagy induction or stimulation of autophagy flux, at least partially, attenuated the B-Fe3O4NP-induced HUVEC dysfunction. Additionally, enhanced autophagic activity might be linked to the B-Fe3O4NP-induced production of proinflammatory cytokines. Taken together, these results demonstrated that B-Fe3O4NPs disturb the process of autophagy in HUVECs, and eventually lead to endothelial dysfunction and inflammation.

  20. Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling

    Science.gov (United States)

    Coll-Bonfill, Núria; Musri, Melina Mara; Ivo, Victor; Barberà, Joan Albert; Tura-Ceide, Olga

    2015-01-01

    Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington’s epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington’s theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality. PMID:25973327

  1. Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling.

    Science.gov (United States)

    Coll-Bonfill, Núria; Musri, Melina Mara; Ivo, Victor; Barberà, Joan Albert; Tura-Ceide, Olga

    2015-01-01

    Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington's epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington's theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality.

  2. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. (Eastern Virginia Medical School, Norfolk (USA))

    1989-11-01

    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  3. Degradable poly(apigenin) polymer inhibits tumor cell adhesion to vascular endothelial cells.

    Science.gov (United States)

    Cochran, David B; Gray, Lindsay N; Anderson, Kimberly W; Dziubla, Thomas D

    2016-10-01

    Cancer and the inflammatory system share a complex intertwined relationship. For instance, in response to an injury or stress, vascular endothelial cells will express cell adhesion molecules as a means of recruiting leukocytes. However, circulating tumor cells (CTCs) have been shown to highjack this expression for the adhesion and invasion during the metastatic cascade. As such, the initiation of endothelial cell inflammation, either by surgical procedures (cancer resection) or chemotherapy can inadvertently increase the metastatic potential of CTCs. Yet, systemic delivery of anti-inflammatories, which weaken the entire immune system, may not be preferred in some treatment settings. In this work, we demonstrate that a long-term releasing flavone-based polymer and subsequent nanoparticle delivery system can inhibit tumor cell adhesion, through the suppression of endothelial cell adhesion molecule expression. The degradation of a this anti-inflammatory polymer provides longer term, localized release profile of active therapeutic drug in nanoparticle form as compared with that of the free drug, permitting more targeted anti-metastatic therapies. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1438-1447, 2016.

  4. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Weidemann AK

    2013-09-01

    Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

  5. The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells.

    Science.gov (United States)

    Absi, Mais; Bruce, Jason I; Ward, Donald T

    2014-04-01

    Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.

  6. Inhibition of the proliferation and acceleration of migration of vascular endothelial cells by increased cysteine-rich motor neuron 1

    Energy Technology Data Exchange (ETDEWEB)

    Nakashima, Yukiko; Morimoto, Mayuka [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Toda, Ken-ichi [Department of Dermatology, Kitano Hospital, The Tazuke Kofukai Nedical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480 (Japan); Shinya, Tomohiro; Sato, Keizo [Department of Clinical Biochemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Miyazaki 882-8508 (Japan); Takahashi, Satoru, E-mail: imwalrus@mukogawa-u.ac.jp [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Institute for Biosciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan)

    2015-07-03

    Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. - Highlights: • CRIM1 was upregulated only in tubular endothelial cells, but not in monolayers. • Increased CRIM1 reduced the proliferation of endothelial cells. • Increased CRIM1 accelerated the migration of endothelial cells. • Increased CRIM1 had no effect on the proliferation or migration of COS-7 cells.

  7. Effects of Quyu Xiaoban Capsule(祛瘀消斑胶囊) on Vascular Endothelial Function in Patients with Atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    LIU Yun-fang; ZHAO Yu-xia; Yu Hui-ming

    2006-01-01

    Objective: To evaluate the therapeutic effects of Quyu Xiaoban Capsule (祛瘀消斑胶囊 ,QYXBC) on endothelial dependent vascular relaxation (EDVR) function in patients with atherosclerosis (AS)with ultrasonic technique. Methods: Tested were the endothelial function and blood lipids of 42 patients with AS in the treated group and 30 healthy volunteers in the control group. And re-examination of these parameters was carried out on the AS patients after they had been treated with QYXBC for 10 months. Results: Before treatment, the reactive hyperemia induced changes in artery diameter in the treated group was significantly lower than that in the control group (P<0.01), while insignificant difference was found between the two groups in response to nitroglycerin. In the treated group after treatment, with D%-R improved significantly (P<0.01), total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C)decreased by 16.3%, 5.6%, 10.2% respectively and high-density lipoprotein cholesterol (HDL-C) increased by 7.5%. EDVR was correlated negatively with the serum TC, LDL-C concentrations and the baseline brachial diameter (D0) (r = -0.41, -0.66, -0.59, respectively, all P<0.01), but correlated positively with HDL-C (r = 0.62, P<0.05). The ameliorative extent of EDVR was correlated positively to the decreased magnitude of TC and LDL-C concentrations ( r = 0.67,0.59, both P<0.01 ). Conclusion: QYXBC can lower the level of blood lipids and improve significantly EDVR function.

  8. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Sarah H McBride

    Full Text Available The importance of bone morphogenetic protein 2 (BMP2 in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre. Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young's modulus (greater than 35% but decreased post-yield displacement (greater than 50% at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.

  9. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells.

    Science.gov (United States)

    McBride, Sarah H; McKenzie, Jennifer A; Bedrick, Bronwyn S; Kuhlmann, Paige; Pasteris, Jill D; Rosen, Vicki; Silva, Matthew J

    2014-01-01

    The importance of bone morphogenetic protein 2 (BMP2) in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre) and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre). Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately) would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young's modulus (greater than 35%) but decreased post-yield displacement (greater than 50%) at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.

  10. Expression of GLI1 correlates with expression of lymphangiogenesis proteins, vascular endothelial growth factor C and vascular endothelial growth factor receptor 3, in colorectal cancer.

    Science.gov (United States)

    Hong, Kwang Dae; Lee, Youngseok; Kim, Baek-Hui; Lee, Sun Il; Moon, Hong Young

    2013-02-01

    Aberrant activation of the hedgehog (Hh) signaling pathway is associated with tumorigenesis in various tissues. In colorectal cancer (CRC), evidence for Hh activation is inconsistent, and the relationship between the Hh signaling pathway and lymphangiogenesis has not been studied. The aim of this study was to determine the relationship between Hh signaling and lymphangiogenesis and the association of this relationship with lymph node metastasis in CRC. We investigated 189 patients who underwent curative surgical resection for CRC between 2002 and 2004 at Korea University Guro Hospital. Paraffin-embedded specimens of colorectal adenocarcinoma and adjacent normal mucosa were evaluated. Immunohistochemical staining for Sonic hedgehog (Shh), Gli1, vascular endothelial growth factor C (VEGFC), and VEGF receptor 3 (VEGFR3) was performed for each specimen. Tumor specimen showed significantly strong staining of Shh, Gli1, VEGFC, and VEGFR3 compared with a normal specimen. Shh expression was not associated with Gli1 expression. Gli1 expression correlated positively with VEGFC and VEGFR3 expression (P < 0.05 in both) but not with lymph node metastasis. Activation of the Hh signaling pathway associated with Gli1 promotes expression of lymphangiogenesis proteins, VEGFC and VEGFR3, in CRC. Further studies are necessary to determine the association of this relationship with lymph node metastasis in CRC.

  11. Benfotiamine attenuates nicotine and uric acid-induced vascular endothelial dysfunction in the rat.

    Science.gov (United States)

    Balakumar, Pitchai; Sharma, Ramica; Singh, Manjeet

    2008-01-01

    The study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in nicotine and uric acid-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg kg(-1)day(-1), i.p., 4 weeks) and uric acid (150 mg kg(-1)day(-1), i.p., 3 weeks) were administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy (SEM) of thoracic aorta. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of nicotine and uric acid produced VED by impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic concentration of nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine and uric acid produced oxidative stress, which was assessed in terms of increase in serum TBARS and aortic superoxide generation. However, treatment with benfotiamine (70 mg kg(-1)day(-1), p.o.) or atorvastatin (30 mg kg(-1)day(-1) p.o., a standard agent) markedly prevented nicotine and uric acid-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that benfotiamine reduces the oxidative stress and consequently improves the integrity of vascular endothelium and enhances the generation of nitric oxide to prevent nicotine and uric acid-induced experimental VED.

  12. Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF and apoptosis in fetal adrenal glands

    Directory of Open Access Journals (Sweden)

    T. Karaca

    2015-11-01

    Full Text Available This study investigated the expression of vascular endothelial growth factor (VEGF, vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0 was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis. 

  13. Possible vasculoprotective role of linagliptin against sodium arsenite-induced vascular endothelial dysfunction.

    Science.gov (United States)

    Jyoti, Uma; Kansal, Sunil Kumar; Kumar, Puneet; Goyal, Sandeep

    2016-02-01

    Vascular endothelial dysfunction (VED) interrupts the integrity and function of endothelial lining through enhanced markers of oxidative stress and decrease endothelial nitric oxide synthase (eNOS) expression. The main aim of the present study has been designed to investigate the possible vasculoprotective role of linagliptin against sodium arsenite-induced VED. Sodium arsenite (1.5 mg/kg, i.p., 2 weeks) abrogated the acetylcholine-induced, endothelium-dependent vasorelaxation by depicting the decrease in serum nitrite/nitrate concentration, reduced glutathione level, and simultaneously enhance the thiobarbituric acid reactive substances (TBARS) level, superoxide level, and tumor necrosis factor-alpha. These elevated markers interrupt the integrity of endothelial lining of thoracic aorta which was assessed histologically. The study elicits dose dependent effect of linagliptin (1.5 mg/kg, i.p. and 3 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) treatment, improved the endothelium-dependent independent relaxation, improve the integrity of endothelium lining which was assessed histologically by enhancing the serum nitrite/nitrate level, reduced glutathione level and simultaneously decreasing the TBARS level, superoxide anion level and tumor necrosis factor-alpha (TNF-α) level. L-NAME (25 mg/kg, i.p.), eNOS inhibitor, abrogated the ameliorative potential of linagliptin. However, the ameliorative potential of linagliptin has been enhanced by l-arginine (200 mg/kg, i.p.) which elicits that ameliorative potential of linagliptin was through eNOS signaling cascade and it may be concluded that linagliptin 3 mg/kg, i.p. has more significantly activated the eNOS and decreased the oxidative markers than linagliptin 1.5 mg/kg, i.p. and prevented sodium arsenite-induced VED.

  14. Gomisin J from Schisandra chinensis induces vascular relaxation via activation of endothelial nitric oxide synthase.

    Science.gov (United States)

    Park, Ji Young; Choi, Young Whan; Yun, Jung Wook; Bae, Jin Ung; Seo, Kyo Won; Lee, Seung Jin; Park, So Youn; Kim, Chi Dae

    2012-01-01

    Gomisin J (GJ) is a lignan contained in Schisandra chinensis (SC) which is a well-known medicinal herb for improvement of cardiovascular symptoms in Korean. Thus, the present study examined the vascular effects of GJ, and also determined the mechanisms involved. Exposure of rat thoracic aorta to GJ (1-30μg/ml) resulted in a concentration-dependent vasorelaxation, which was more prominent in the endothelium (ED)-intact aorta. ED-dependent relaxation induced by GJ was markedly attenuated by pretreatment with L-NAME, a nitric oxide synthase (NOS) inhibitor. In the intact endothelial cells of rat thoracic aorta, GJ also enhanced nitric oxide (NO) production. In studies using human coronary artery endothelial cells, GJ enhanced phosphorylation of endothelial NOS (eNOS) at Ser(1177) with increased cytosolic translocation of eNOS, and subsequently increased NO production. These effects of GJ were attenuated not only by calcium chelators including EGTA and BAPTA-AM, but also by LY294002, a PI3K/Akt inhibitor, indicating calcium- and PI3K/Akt-dependent activation of eNOS by GJ. Moreover, the levels of intracellular calcium were increased immediately after GJ administration, but Akt phosphorylation was started to increase at 20min of GJ treatment. Based on these results with the facts that ED-dependent relaxation occurred rapidly after GJ treatment, it was suggested that the ED-dependent vasorelaxant effects of GJ were mediated mainly by calcium-dependent activation of eNOS with subsequent production of endothelial NO.

  15. Overexpression of Vascular Endothelial Growth Factor in Restenotic Abdominal Aorta of Rabbits

    Institute of Scientific and Technical Information of China (English)

    尹瑞兴; 杨德寨; 吴海; 黄凯; 巫相宏; 陈宇明

    2002-01-01

    Objective To investigatethe expression of vascular endothelial growth factor (VEGF) in the wall of normal and restenotic abdominal aorta of rabbits. Methods Restenotic model was developed by balloon-injured abdominal aorta in eight male New Zealand White rabbits fed with a 2.0% cholesterol diet beginning two weeks before operation and continuing four weeks after procedure. At the end of 4 weeks after injury, the animals underwent total body perfusion fixation. Then, the abdominal aorta from iliac artery root to the diaphragm was harvested and post-fixed in 10 % neutral formalin for 16hours. Eight male animals fed with general diet were used for a normal control. The VEGF protein level in normal and restenotic abdominal aorta of rabbits was studied by means of immunohistochemistry. Results VEGF protein was detected in 5 (62.5 % ) of 8normal abdominal aorta, 3 showed faint staining, and the remaining 2 showed moderate VEGF expression.VEGF expression at the protein level was identified in all 8 restenotic specimens, 2 showed faint staining, 4showed moderate staining, and the remaining 2showed strong VEGF expression. In contrast to normal vessels, VEGF in restenotic specimens was distinctly expressed at sites that contained clustered macrophages and proliferating smooth muscle cells as well as endothelial cells. VEGF immunostaining was more extensive in restenotic specimens (2. 00 ± 0.76)than in normal vessels (0.82 ±0. 83, P < 0.01) .Microvessels were found in 7 of the 8 restenotic lesions, but only one lesion showed VEGF staining in endothelial cells of the microvessels. Conclusion VEGF expression is consistently more intense in sections of restenotic abdominal aorta than in those of normal abdominal aorta. The VEGF expressed by the smooth muscle cells and foamy macrophages in the restenotic arteries may act as a local and endogenous regulator of endothelial cell functions, including maintenance and repair of luminal endothelium, and formation of intimal

  16. Human umbilical cord blood-derived mesenchymal stem cells promote vascular growth in vivo.

    Directory of Open Access Journals (Sweden)

    Santiago Roura

    Full Text Available Stem cell therapies are promising strategies to regenerate human injured tissues, including ischemic myocardium. Here, we examined the acquisition of properties associated with vascular growth by human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs, and whether they promoted vascular growth in vivo. UCBMSCs were induced in endothelial cell-specific growth medium (EGM-2 acquiring new cell markers, increased Ac-LDL uptake, and migratory capacity as assessed by qRT-PCR, Western blotting, indirect immunofluorescence, and invasion assays. Angiogenic and vasculogenic potentials could be anticipated by in vitro experiments showing self organization into Matrigel-mediated cell networks, and activation of circulating angiogenic-supportive myeloid cells. In mice, following subcutaneous co-injection with Matrigel, UCBMSCs modified to co-express bioluminescent (luciferases and fluorescent proteins were demonstrated to participate in the formation of new microvasculature connected with the host circulatory system. Response of UCBMSCs to ischemia was explored in a mouse model of acute myocardial infarction (MI. UCBMSCs transplanted using a fibrin patch survived 4 weeks post-implantation and organized into CD31(+network structures above the infarcted myocardium. MI-treated animals showed a reduced infarct scar and a larger vessel-occupied area in comparison with MI-control animals. Taken together, the presented results show that UCBMSCs can be induced in vitro to acquire angiogenic and vasculogenic properties and contribute to vascular growth in vivo.

  17. Effect of ozone on vascular endothelial growth factor (VEGF) and related inflammatory cytokines in rats with diabetic retinopathy.

    Science.gov (United States)

    Xie, T Y; Yan, W; Lou, J; Chen, X Y

    2016-05-13

    The aim of this study was to investigate the effect of ozone on inflammatory cytokines in diabetic retinopathy (DR) rats. Male rats (40) weighing 300-360 g were included in this study. Thirty rats were randomly divided into the model and ozone groups after DR was induced by streptozotocin. Ten rats served as the blank group. After the diabetic models were established for one month, the rats in the ozone group were treated with 50 mg/kg ozone coloclysis for one month (three times a week). After the rats were anesthetized by intraperitoneal injection, blood samples from the abdominal aorta were collected, and the supernatant was obtained by centrifugation. Vascular endothelial growth factor (VEGF) and inflammatory cytokine content in the serum was detected by enzyme linked immunosorbent assay. The values of VEGF, intercellular cell adhesion molecule-1, interleukin-1 beta, tumor necrosis factor-a, and IL-6 were significantly different among the three groups (P ozone group was higher than that in the blank group. Compared with the model group, the cytokine levels in the ozone group were significantly reduced (P Ozone had no effect on the blood glucose of diabetic rats. Treatment with ozone coloclysis may effectively reduce the secretion of VEGF and inflammatory cytokines in diabetic retinopathy rats.

  18. Effect of systemic piracetam treatment on flap survival and vascular endothelial growth factor expression after ischemia-reperfusion injury.

    Science.gov (United States)

    Tuncer, Serhan; Ayhan, Suhan; Findikcioglu, Kemal; Ergun, Hakan; Tuncer, Ilhan

    2011-09-01

    The effects of piracetam on flap survival, ischemia-reperfusion (I/R) injury, and vascular endothelial growth factor (VEGF) expression were evaluated in this study. Unipedicled epigastric flap model was used in 36 rats and was evaluated within 4 groups. The flap was elevated and untreated in Group 1. Postoperative piracetam treatment was given for 7 days in Group 2. In Group 3, 4 hours of ischemia and 2 hours of reperfusion were applied. I/R was applied to Group 4 and piracetam was given 30 minutes before reperfusion and postoperatively for 7 days. Laser Doppler flowmetry was used to measure blood flow changes. VEGF expression was determined using immunohistochemical methods on tissue samples taken after the completion of 2 hours reperfusion in groups 3 and 4. Flap necrosis was measured on the day 7 in all groups. Blood flow rates did not show significant difference between piracetam treated and untreated I/R groups. Piracetam significantly reduced necrosis area both in ischemic and nonischemic flaps ( P piracetam-treated Group 4 compared with Group 3 ( P = 0.005). This experimental study demonstrates that systemic piracetam treatment improves survival of pedicled flaps, reduces necrosis amounts, and increases VEGF expression in I/R induced flaps.

  19. Reprint of "The role of cytoskeleton in the regulation of vascular endothelial barrier function" [Microvascular Research 76 (2008) 202-207].

    Science.gov (United States)

    Bogatcheva, Natalia V; Verin, Alexander D

    2009-01-01

    The cytoskeleton is vital to the function of virtually all cell types in the organism as it is required for cell division, cell motility, endo- or exocytosis and the maintenance of cell shape. Endothelial cells, lining the inner surface of the blood vessels, exploit cytoskeletal elements to ensure the integrity of cell monolayer in quiescent endothelium, and to enable the disintegration of the formed barrier in response to various agonists. Vascular permeability is defined by the combination of transcellular and paracellular pathways, with the latter being a major contributor to the inflammation-induced barrier dysfunction. This review will analyze the cytoskeletal elements, which reorganization affects endothelial permeability, and emphasize signaling mechanisms with barrier-protective or barrier-disruptive potential.

  20. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish.

    Science.gov (United States)

    Ando, Koji; Fukuhara, Shigetomo; Izumi, Nanae; Nakajima, Hiroyuki; Fukui, Hajime; Kelsh, Robert N; Mochizuki, Naoki

    2016-04-15

    Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs.

  1. Involvement of vascular endothelial growth factor in nasal obstruction in patients with nasal allergy

    Directory of Open Access Journals (Sweden)

    Tetsuji Yamashita

    2000-01-01

    Full Text Available It has recently been shown that vascular endothelial growth factor (VEGF enhances vascular permeability and that mast cells produce VEGF, suggesting the involvement of VEGF in allergic diseases. In the present study we quantitatively analyzed VEGF in the nasal lavage fluid of patients with nasal allergy. We performed nasal antigen challenge with Japanese cedar pollen antigen in 10 healthy adult volunteers and in 10 cedar pollen IgE-positive patients with nasal allergy. In all patients with nasal allergy, VEGF and histamine levels in the nasal lavage fluid reached a peak 30 min after antigen challenge, then returned to prechallenge values 2 h after antigen challenge. In these patients, the histamine level increased three-fold, while the VEGF level increased 10-fold. However, in all healthy adult volunteers, VEGF and histamine levels did not increase. A stronger correlation was noted between the ratio of decreased nasal cavity volume and the ratio of increased VEGF levels (R = 0.823; P < 0.001 than between the ratio of nasal cavity volume and the ratio of increased histamine levels (R = 0.660; P < 0.01. These results suggest that VEGF may contribute to the pathogenesis of nasal obstruction in the early phase of nasal allergy as a new factor involved in increasing vascular permeability.

  2. Endothelial Progenitor Cell Dysfunction in Myelodysplastic Syndromes: Possible Contribution of a Defective Vascular Niche to Myelodysplasia

    Directory of Open Access Journals (Sweden)

    Luciana Teofili

    2015-05-01

    Full Text Available We set a model to replicate the vascular bone marrow niche by using endothelial colony forming cells (ECFCs, and we used it to explore the vascular niche function in patients with low-risk myelodysplastic syndromes (MDS. Overall, we investigated 56 patients and we observed higher levels of ECFCs in MDS than in healthy controls; moreover, MDS ECFCs were found variably hypermethylated for p15INK4b DAPK1, CDH1, or SOCS1. MDS ECFCs exhibited a marked adhesive capacity to normal mononuclear cells. When normal CD34+ cells were co-cultured with MDS ECFCs, they generated significant lower amounts of CD11b+ and CD41+ cells than in co-culture with normal ECFCs. At gene expression profile, several genes involved in cell adhesion were upregulated in MDS ECFCs, while several members of the Wingless and int (Wnt pathways were underexpressed. Furthermore, at miRNA expression profile, MDS ECFCs hypo-expressed various miRNAs involved in Wnt pathway regulation. The addition of Wnt3A reduced the expression of intercellular cell adhesion molecule-1 on MDS ECFCs and restored the defective expression of markers of differentiation. Overall, our data demonstrate that in low-risk MDS, ECFCs exhibit various primary abnormalities, including putative MDS signatures, and suggest the possible contribution of the vascular niche dysfunction to myelodysplasia.

  3. Vascular endothelial growth factor in skeletal muscle following glycogen-depleting exercise in humans

    DEFF Research Database (Denmark)

    Jensen, Line

    2015-01-01

    Vascular endothelial growth factor (VEGF) is traditionally considered important for skeletal muscle angiogenesis. VEGF is released from vascular endothelium as well as the muscle cells in response to exercise. The mechanism and the physiological role of VEGF secreted from the muscle cells remain...... unclear. However, as VEGF is also considered very important for the regulation of vascular permeability, it is possible that metabolic stress may trigger muscle VEGF release. PURPOSE: To study the role of metabolic stress induced by glycogen-depleting exercise on muscle VEGF expression. METHODS: Fifteen...... males (age 27.0±0.8; VO2max 66.0±1.2 ml•kg-1•min-1) carried out 4h of cycling exercise supplied with H2O only followed by 4h of recovery with either carbohydrate (CHO) (n=8) or H2O (n=7) supplementation. Hereafter both groups received CHO. Muscle biopsies were collected pre and post as well as 4 and 24...

  4. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish

    Science.gov (United States)

    Ando, Koji; Fukuhara, Shigetomo; Izumi, Nanae; Nakajima, Hiroyuki; Fukui, Hajime; Kelsh, Robert N.; Mochizuki, Naoki

    2016-01-01

    Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo. To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs. PMID:26952986

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-25

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

  6. Heparin and Vascular Endothelial Growth Factor Loaded Poly(L-lactide-co-caprolactone) Nanofiber Covered Stent-Graft for Aneurysm Treatment.

    Science.gov (United States)

    Wang, Jing; An, Qingzhu; Li, Dawei; Wu, Tong; Chen, Weiming; Sun, Binbin; El-Hamshary, Hany; Al-Deyab, Salem S; Zhu, Wei; Mo, Xiumei

    2015-11-01

    Restenosis caused by thrombopoiesis is one of the biggest hinders of endovascular stent-graft used in small-diameter vessels. Rapid endothelialization of the lumen of stent is a promising approach to prevent thrombosis. In this study, we aimed at loading heparin, a potent anticoagulants, and vascular endothelial growth factor (VEGF) into the core of poly(L-lactide-co-caprolactone) nanofiber via emulsion electrospinning. The nanofiber was covered on the stent and applied in the treatment of vascular diseases such as aneurysm. The morphologies of the emulsion electrospun nanofibers and core--shell structure were observed by scanning electron microscope and laser scanning confocal microscope. The release profiles of heparin and VEGF, degradation rate of nanofiber mats and cell proliferation in vitro were investigated. It was found that the release of both heparin and VEGF from the nanofiber lasted for more than 30 days without serious initial burst release. The degradation rate of nanofiber mats containing heparin and VEGF was faster than that of pure PLCL nanofiber mats. Moreover, the released VEGF could promote the proliferation of Pig iliac endothelial cells (PIECs) cultured on the nanofiber mat, which was of great benefit to stent endothelialization. The results of digital subtraction angiography (DSA) follow-up indicated the aneurysm was obliterated by separating the aneurysm dome from the blood circulation and the parent artery kept long-term patency. Results of the study demonstrated that the heparin and VEGF loaded nanofiber could provide an approach to fabricate covered stent-graft with properties of anticoagulation and induction of rapid endothelialization.

  7. α-fetoprotein, vascular endothelial growth factor receptor-1 and early recurrence of hepatoma

    Institute of Scientific and Technical Information of China (English)

    Toshiya Kamiyama; Masato Takahashi; Kazuaki Nakanishi; Hideki Yokoo; Hirofumi Kamachi; Nozomi Kobayashi; Michitaka Ozaki; Satoru Todo

    2012-01-01

    AIM: To investigate whether α-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR)-1 correlate with early recurrence of hepatoma/hepatocellular carcinoma (HCC). METHODS: From 2000 to 2005, 114 consecutive patients with HCC underwent primary curative hepatectomy. The mean age was 60.7 (8.7) years and 94 patients were male. The median follow-up period was 71.2 mo (range: 43-100 mo). Immediately prior to commencing laparotomy, 5 mL bone marrow was aspirated from thesternum and collected in citrate-coated test tubes. The initial 2 mL of bone marrow aspirate was discarded in each case. AFP mRNA and VEGFR-1 mRNA in the bone marrow and peripheral blood (BM-and PH-AFP mRNA and BM-and PH-VEGFR-1 mRNA, respectively) were measured by real-time quantitative reverse transcription polymerase chain reaction. As normal controls, VEGFR-1 mRNA in the bone marrow and peripheral blood was also measured in 11 living liver donors. These data were evaluated for any correlation with early recurrence, comparing clinical and pathological outcomes. RESULTS: The cut-off value of the BM-AFP mRNA and PH-AFP mRNA level in patients with HCC was set at 1.92 × 10-7 and zero, respectively, based on data from the controls. A total of 34 (29.8%) and six (5.4%) patients were positive for BM-AFP mRNA and PH-AFP mRNA, respectively. The BM-VEGFR-1 mRNA levels in all HCC patients were higher than those in the normal controls, and this was the case also for PH-VEGFR-1mRNA. The 25-percentile values for the BM-and PH-VEGFR-1 mRNA in HCC patients were used as the cut-off values for assigning the patients into two groups based on these transcript levels. The High group for BM-VEGFR-1 mRNA contained 81 (71.1%) HCC cases and the Low group was assigned 33 (28.9%) patients. These numbers for PH-VEGFR-1mRNA were 78 (75.0%) and 26 (25.0%), respectively. HCC recurred in 80 patients; in the remnant liver in 48 cases, in the remnant liver and remote tissue in 20, and in the remote tissue alone in

  8. Influence of mild hypothermia on vascular endothelial growth factor and infarct volume in brain tissues after cerebral ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Ye; Gangming Xi; Biyong Qin; Shifeng Wang; Chengyan Li

    2006-01-01

    BACKGROUND: It has been demonstrated that mild hypothermia has obvious protective effect on both whole and local cerebral ischemia. However, the definite mechanism is still unclear for the brain protection of mild hypothermia on cerebral edema, inhibiting inflammatory reaction, stabilizing blood brain barrier, etc.OBJECTIVE: To investigate the effect of mild hypothermia on the expression of vascular endothelial growth factor and the infarct volume after cerebral ischemia in rats, and analyze the brain protective mechanism of mild hypothermia.DESIGN: A randomized grouping and controlled animal trial.SETTING: Department of Neurology, People's Hospital of Yunyang Medical College.MATERIALS: Twenty adult male SD rats of clean degree, weighing (250±30) g, were provided by the animal experimental center, School of Medicine, Wuhan University. The kits for SP immunohistochemistry were purchased from Beijing Zhongshan Golden Bridge Biotechnology Co., Ltd.METHODS: The experiments were carried out in the laboratory of Department of Neurology, Renmen Hospital of Wuhan University from May to July 2005. ① The 20 rats were divided randomly into normal temperature group (n =10) and mild hypothermia group (n =10). Models of permanent middle cerebral artery occlusion were established with modified nylon suture embolization. The rats were assessed with the Longa standards: O point for without nerve dysfunction; 1 for mild neurological deficit (fore claws could no extend completely); 2 for moderate neurological deficit (circling towards the affected side); 3 for severe neurological deficit (tilting towards the affected side); 4 for coma and unconscious; 1 -3 points represented that models were successfully established. The rats of the normal temperature group were fed at room temperature, and those in the mild hypothermia group were induced by hypothermia from 2 hours postoperatively, and the rectal temperature was kept at 34-35 ℃ for 72 hours. ② Measurement of infarct volume

  9. Histone Deacetylase (HDAC Inhibitors Down-Regulate Endothelial Lineage Commitment of Umbilical Cord Blood Derived Endothelial Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Horia Maniu

    2012-11-01

    Full Text Available To test the involvement of histone deacetylases (HDACs activity in endothelial lineage progression, we investigated the effects of HDAC inhibitors on endothelial progenitors cells (EPCs derived from umbilical cord blood (UCB. Adherent EPCs, that expressed the endothelial marker proteins (PCAM-1, CD105, CD133, and VEGFR2 revealed by flow cytometry were treated with three HDAC inhibitors: Butyrate (BuA, Trichostatin A (TSA, and Valproic acid (VPA. RT-PCR assay showed that HDAC inhibitors down-regulated the expression of endothelial genes such as VE-cadherin, CD133, CXCR4 and Tie-2. Furthermore, flow cytometry analysis illustrated that HDAC inhibitors selectively reduce the expression of VEGFR2, CD117, VE-cadherin, and ICAM-1, whereas the expression of CD34 and CD45 remained unchanged, demonstrating that HDAC is involved in endothelial differentiation of progenitor cells. Real-Time PCR demonstrated that TSA down-regulated telomerase activity probably via suppression of hTERT expression, suggesting that HDAC inhibitor decreased cell proliferation. Cell motility was also decreased after treatment with HDAC inhibitors as shown by wound-healing assay. The balance of acethylation/deacethylation kept in control by the activity of HAT (histone acetyltransferases/HDAC enzymes play an important role in differentiation of stem cells by regulating proliferation and endothelial lineage commitment.

  10. The Effects of Smoking on Levels of Endothelial Progenitor Cells and Microparticles in the Blood of Healthy Volunteers

    Science.gov (United States)

    Mobarrez, Fariborz; Antoniewicz, Lukasz; Bosson, Jenny A.; Kuhl, Jeanette; Pisetsky, David S.; Lundbäck, Magnus

    2014-01-01

    Background Cigarette smoking, both active and passive, is one of the leading causes of morbidity and mortality in cardiovascular disease. To assess the impact of brief smoking on the vasculature, we determined levels of circulating endothelial progenitor cells (EPCs) and circulating microparticles (MPs) following the smoking of one cigarette by young, healthy intermittent smokers. Materials and Methods 12 healthy volunteers were randomized to either smoking or not smoking in a crossover fashion. Blood sampling was performed at baseline, 1, 4 and 24 hours following smoking/not smoking. The numbers of EPCs and MPs were determined by flow cytometry. MPs were measured from platelets, leukocytes and endothelial cells. Moreover, MPs were also labelled with anti-HMGB1 and SYTO 13 to assess the content of nuclear molecules. Results Active smoking of one cigarette caused an immediate and significant increase in the numbers of circulating EPCs and MPs of platelet-, endothelial- and leukocyte origin. Levels of MPs containing nuclear molecules were increased, of which the majority were positive for CD41 and CD45 (platelet- and leukocyte origin). CD144 (VE-cadherin) or HMGB1 release did not significantly change during active smoking. Conclusion Brief active smoking of one cigarette generated an acute release of EPC and MPs, of which the latter contained nuclear matter. Together, these results demonstrate acute effects of cigarette smoke on endothelial, platelet and leukocyte function as well as injury to the vascular wall. PMID:24587320

  11. The effects of smoking on levels of endothelial progenitor cells and microparticles in the blood of healthy volunteers.

    Directory of Open Access Journals (Sweden)

    Fariborz Mobarrez

    Full Text Available BACKGROUND: Cigarette smoking, both active and passive, is one of the leading causes of morbidity and mortality in cardiovascular disease. To assess the impact of brief smoking on the vasculature, we determined levels of circulating endothelial progenitor cells (EPCs and circulating microparticles (MPs following the smoking of one cigarette by young, healthy intermittent smokers. MATERIALS AND METHODS: 12 healthy volunteers were randomized to either smoking or not smoking in a crossover fashion. Blood sampling was performed at baseline, 1, 4 and 24 hours following smoking/not smoking. The numbers of EPCs and MPs were determined by flow cytometry. MPs were measured from platelets, leukocytes and endothelial cells. Moreover, MPs were also labelled with anti-HMGB1 and SYTO 13 to assess the content of nuclear molecules. RESULTS: Active smoking of one cigarette caused an immediate and significant increase in the numbers of circulating EPCs and MPs of platelet-, endothelial- and leukocyte origin. Levels of MPs containing nuclear molecules were increased, of which the majority were positive for CD41 and CD45 (platelet- and leukocyte origin. CD144 (VE-cadherin or HMGB1 release did not significantly change during active smoking. CONCLUSION: Brief active smoking of one cigarette generated an acute release of EPC and MPs, of which the latter contained nuclear matter. Together, these results demonstrate acute effects of cigarette smoke on endothelial, platelet and leukocyte function as well as injury to the vascular wall.

  12. Sanguis draconis, a Dragon’s Blood Resin, Attenuates High Glucose-Induced Oxidative Stress and Endothelial Dysfunction in Human Umbilical Vein Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Yi Chang

    2014-01-01

    Full Text Available Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD, a kind of dragon’s blood resin that is obtained from Daemonorops draco (Palmae, on human umbilical vein endothelial cells (HUVEC under high-glucose (HG stimulation and its underlying mechanism. Concentration-dependent (0–50 μg/mL assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10–50 μg/mL significantly attenuated the high-glucose (25 and 50 mM induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO and lipid peroxidation (MDA production and reactive oxygen species (ROS formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2, nuclear transcription factor, κB (NF-κB, VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation.

  13. Nafamostat Mesilate Inhibits TNF-α-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production.

    Science.gov (United States)

    Kang, Min-Woong; Song, Hee-Jung; Kang, Shin Kwang; Kim, Yonghwan; Jung, Saet-Byel; Jee, Sungju; Moon, Jae Young; Suh, Kwang-Sun; Lee, Sang Do; Jeon, Byeong Hwa; Kim, Cuk-Seong

    2015-05-01

    Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-α (TNF-α). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 µg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-α (3 ng/mL), and it dose dependently prevented the TNF-α-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-α-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-α-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.

  14. Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor)

    Energy Technology Data Exchange (ETDEWEB)

    Winkles, J.A.; Friesel, R.; Burgess, W.H.; Howk, R.; Mehlman, T.; Weinstein, R.; Maciag, T.

    1987-10-01

    The control of vascular endothelial and muscle cell proliferation is important in such processes as tumor angiogenesis, wound healing, and the pathogenesis of atherosclerosis. Class I heparin-binding growth factor (HBGF-I) is a potent mitogen and chemoattractant for human endothelial cells in vitro and will induce angiogenesis in vivo. RNA gel blot hybridization experiments demonstrate that cultured human vascular smooth muscle cells, but not human umbilical cells also synthesize an HBGF-I mRNA. Smooth muscle cells also synthesize an HBGF-I-like polypeptide since (i) extract prepared from smooth muscle cells will compete with /sup 125/I-labeled HBGF-I for binding to the HBGF-I cell surface receptor, and (ii) the competing ligand is eluted from heparin-Sepharose affinity resin at a NaCl concentration similar to that required by purified bovine brain HBGF-I and stimulates endothelial cell proliferation in vitro. Furthermore, like endothelial cells, smooth muscle cells possess cell-surface-associated HBGF-I receptors and respond to HBGF-I as a mitogen. These results indicate the potential for an additional autocrine component of vascular smooth muscle cell growth control and establish a vessel wall source of HBGF-I for endothelial cell division in vivo.

  15. Effect of rosiglitazone in sodium arsenite-induced experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Kaur, Tajpreet; Goel, Rajesh Kumar; Balakumar, Pitchai

    2010-04-01

    The present study has been designed to investigate the effect of rosiglitazone, a peroxisome proliferator activated receptor gamma agonist in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. The rats were administered sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) to induce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum nitrite/nitrate concentration. Further, the integrity of the aortic endothelium was assessed histologically using haematoxylin-eosin staining. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances, aortic reactive oxygen species and reduced form of glutathione. The administration of sodium arsenite produced VED by impairing acetylcholine-induced endothelium dependent relaxation, diminishing the integrity of vascular endothelium and decreasing the serum nitrite/nitrate concentration. In addition, sodium arsenite was noted to produce oxidative stress as it increased serum thiobarbituric acid reactive substances and aortic reactive oxygen species and consequently decreased glutathione. Treatment with rosiglitazone (3 mg/kg/day, p.o., 2 weeks and 5 mg/kg/day, p.o., 2 weeks) significantly prevented sodium arsenite-induced VED by enhancing acetylcholine-induced endothelium dependent relaxation, improving the integrity of vascular endothelium, increasing the nitrite/nitrate concentration and decreasing the oxidative stress. However, the vascular protective effect of rosiglitazone was markedly abolished by co-administration of nitric oxide synthase inhibitor, N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME) (25 mg/kg/day, i.p., 2 weeks). Thus, it may be concluded that rosiglitazone reduces oxidative stress, activates eNOS and enhances the generation of nitric oxide to prevent sodium arsenite-induced VED in rats.

  16. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement

    NARCIS (Netherlands)

    G.L. van Sluis; T.M.H. Niers; C.T. Esmon; W. Tigchelaar; D.J. Richel; H.R. Buller; C.J.F. van Noorden; C.A. Spek

    2009-01-01

    Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial

  17. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  18. Gene electro transfer of plasmid encoding vascular endothelial growth factor for enhanced expression and perfusion in the ischemic swine heart.

    Science.gov (United States)

    Hargrave, Barbara; Strange, Robert; Navare, Sagar; Stratton, Michael; Burcus, Nina; Murray, Len; Lundberg, Cathryn; Bulysheva, Anna; Li, Fanying; Heller, Richard

    2014-01-01

    Myocardial ischemia can damage heart muscle and reduce the heart's pumping efficiency. This study used an ischemic swine heart model to investigate the potential for gene electro transfer of a plasmid encoding vascular endothelial growth factor for improving perfusion and, thus, for reducing cardiomyopathy following acute coronary syndrome. Plasmid expression was significantly greater in gene electro transfer treated tissue compared to injection of plasmid encoding vascular endothelial growth factor alone. Higher gene expression was also seen in ischemic versus non-ischemic groups with parameters 20 Volts (ptransfer of plasmid encoding vascular endothelial growth factor had increased perfusion in the area at risk compared to control groups. Troponin and creatine kinase increased across all groups, suggesting equivalent ischemia in all groups prior to treatment. Echocardiography was used to assess ejection fraction, cardiac output, stroke volume, left ventricular end diastolic volume, and left ventricular end systolic volume. No statistically significant differences in these parameters were detected during a 2-week time period. However, directional trends of these variables were interesting and offer valuable information about the feasibility of gene electro transfer of vascular endothelial growth factor in the ischemic heart. The results demonstrate that gene electro transfer can be applied safely and can increase perfusion in an ischemic area. Additional study is needed to evaluate potential efficacy.

  19. Anti-angiogenesis effect of generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide on breast cancer in vitro

    Institute of Scientific and Technical Information of China (English)

    Shan-zhi GU; Xin-han ZHAO; Ling-xiao ZHANG; Li LI; Zhi-yu WANG; Min MENG; Gai-li AN

    2009-01-01

    Objective: To study the effects of the generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide (G4PAMAMNEGFASODN) compound on the expressions of vascular endothelial growth factor (VEGF) and its mRNA of breast cancer cells and on the inhibition of vascular endothelial cells. Methods: We examined the morphology of G4PAMAM/VEGFASODN compound and its pH stability, in vitro transfection efficiency and toxicity, and the expressions of VEGF and its mRNA. Methyl thiazolyl tetrazolium assay was used to detect the inhibitory function of the compound on vascular endothelial cells. Results: The compound was about 10 nm in diameter and was homogeneously netlike. From pH 5 to 10, it showed quite a buffered ability. The 48-h transfection rate in the charge ratio of 1:40 was 98.76%, significantly higher than that of the liposome group (P<0.05). None of the transfection products showed obvious toxicity on the cells. The expressions of both VEGF protein and its mRNA after G4PAMAM/VEGFASODN transfection decreased markedly. Conclusion: With a low toxicity, high safety, and high transfection rate, G4PAMAMNEGFASODN could be a promising gene vector. Specifically, it inhibits VEGF gene expression efficiently, laying a basis for further in vivo animal studies.

  20. The impact of vascular endothelial growth factor and basic fibroblast growth factor on cardiac fibroblasts grown under altered gravity conditions

    DEFF Research Database (Denmark)

    Ulbrich, Claudia; Leder, Annekatrin; Pietsch, Jessica

    2010-01-01

    Myocardium is very sensitive to gravitational changes. During a spaceflight cardiovascular atrophy paired with rhythm problems and orthostatic intolerance can occur. The aim of this study was to investigate the impact of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor...

  1. Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Werther, Kim; Sørensen, Steen; Christensen, Ib Jarle;

    2003-01-01

    High preoperative circulating vascular endothelial growth factor (VEGF) is predictive of poor prognosis in patients with colorectal cancer (CRC). However, postoperative circulating VEGF has not yet been evaluated as a prognostic marker in CRC patients. In 318 consecutive patients who had undergone...

  2. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Steffensen, Karina Dahl;

    2012-01-01

    Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions...

  3. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  4. Low-Dose Dextromethorphan, a NADPH Oxidase Inhibitor, Reduces Blood Pressure and Enhances Vascular Protection in Experimental Hypertension

    Science.gov (United States)

    Wu, Tao-Cheng; Chao, Chih-Yu; Lin, Shing-Jong; Chen, Jaw-Wen

    2012-01-01

    Background Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM), a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP) and vascular protection in aged spontaneous hypertensive rats (SHRs). Methodology/Principal Findings Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker) monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells. Conclusions/Significance Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension. PMID:23049937

  5. Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension.

    Directory of Open Access Journals (Sweden)

    Tao-Cheng Wu

    Full Text Available BACKGROUND: Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM, a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP and vascular protection in aged spontaneous hypertensive rats (SHRs. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells. CONCLUSIONS/SIGNIFICANCE: Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension.

  6. Depression and BMI influences the serum vascular endothelial growth factor level

    DEFF Research Database (Denmark)

    Elfving, Betina; Buttenschøn, Henriette N; Foldager, Leslie

    2014-01-01

    Recent studies suggest that the angiogenic cytokine vascular endothelial growth factor (VEGF) is involved in the pathogenesis of depression. However, only a few studies have investigated serum VEGF levels in individuals with depression, or the possible association between genetic variants within...... the VEGF gene and depression. The purpose of the present study was to investigate differences between serum VEGF levels in individuals with depression vs. control individuals, and associations between genetic markers located within VEGF and depression. In addition, determinants of the serum VEGF levels...... were identified. One-hundred and fifty-five depressed subjects and 280 controls were included in the study. All individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Eleven single nucleotide polymorphisms were successfully analysed. VEGF levels were measured...

  7. Enhanced Vascular Endothelial Growth Factor Gene Expression in Ischaemic Skin of Critical Limb Ischaemia Patients

    Directory of Open Access Journals (Sweden)

    Silvia Bleda

    2012-01-01

    Full Text Available Objectives. To perform a quantitative analysis of the vascular endothelial growth factor (VEGF gene transcription in the skin of ischemic legs and provide information for VEGF in the pathogenesis in critical limb ischemia (CLI. Methods. Skin biopsies were obtained from 40 patients with CLI. Control samples came from 44 patients with chronic venous disease. VEGF gene expression was analysed using quantitative polymerase chain reaction. Results. Patients with CLI had higher skin VEGF expression than control group (RQ: 1.3 ± 0.1 versus 1, P=0.04. Conclusions. We found an association between ischemic skin and an elevated VEGF expression in legs from patients with CLI. These data support that the mechanism for VEGF upregulation in hypoxia conditions is intact and acts appropriately in the ischaemic limbs from patients with CLI.

  8. Analysis of Active Components in Salvia Miltiorrhiza Injection Based on Vascular Endothelial Cell Protection

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    Shen Jie

    2014-09-01

    Full Text Available Correlation analysis based on chromatograms and pharmacological activities is essential for understanding the effective components in complex herbal medicines. In this report, HPLC and measurement of antioxidant properties were used to describe the active ingredients of Salvia miltiorrhiza injection (SMI. HPLC results showed that tanshinol, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B, protocatechuic acid and their metabolites in rat serum may contribute to the efficacy of SMI. Assessment of antioxidant properties indicated that differences in the composition of serum powder of SMI caused differences in vascular endothelial cell protection. When bivariate correlation was carried out it was found that salvianolic acid B, tanshinol and protocatechuic aldehyde were active components of SMI because they were correlated to antioxidant properties.

  9. Development of an aptamer-based affinity purification method for vascular endothelial growth factor

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    Maren Lönne

    2015-12-01

    Full Text Available Since aptamers bind their targets with high affinity and specificity, they are promising alternative ligands in protein affinity purification. As aptamers are chemically synthesized oligonucleotides, they can be easily produced in large quantities regarding GMP conditions allowing their application in protein production for therapeutic purposes. Several advantages of aptamers compared to antibodies are described in general within this paper. Here, an aptamer directed against the human Vascular Endothelial Growth Factor (VEGF was used as affinity ligand for establishing a purification platform for VEGF in small scale. The aptamer was covalently immobilized on magnetic beads in a controlled orientation resulting in a functional active affinity matrix. Target binding was optimized by introduction of spacer molecules and variation of aptamer density. Further, salt-induced target elution was demonstrated as well as VEGF purification from a complex protein mixture proving the specificity of protein-aptamer binding.

  10. Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

    DEFF Research Database (Denmark)

    Andersen, Niels Frost; Vogel, Ulla Birgitte; Klausen, Tobias W;

    2012-01-01

    Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression...... and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide....... Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno...

  11. RNA interference-mediated gene silencing of vascular endothelial growth factor in colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To inhibit the expression of vascular endothelial growth factor (VEGF) in colon cancer cell line by RNA interference (RNAi). METHODS: Followed the service of E-RNAi, we designed and constructed two kinds of shRNA expression vectors aiming at the VEGF gene, then transfected them into colon cancer HT29 cells by lipofectamineTM 2000. The level of VEGF mRNA was investigated by RT-PCR and Northern blotting. The protein expression of VEGF was observed by immunofluoresence staining and Western blotting. RESULTS: We got two kinds of VEGF specific shRNA expression vectors which could efficiently inhibit the expression of VEGF in HT29 cells. RT-PCR, Northern blotting, immunofluoresence staining and Western blotting showed that inhibition rate for VEGF expression was up to 42%, 89%, 73% and 82%, respectively. CONCLUSION: The expression of VEGF can be inhibited by RNA interference in HT29 cells.

  12. Vascular endothelial growth factor-A is associated with chronic mountain sickness in the Andean population.

    Science.gov (United States)

    Espinoza, Jose R; Alvarez, Giancarlo; León-Velarde, Fabiola; Preciado, Hugo F Ju; Macarlupu, Jose-Luis; Rivera-Ch, Maria; Rodriguez, Jorge; Favier, Judith; Gimenez-Roqueplo, Anne-Paule; Richalet, Jean-Paul

    2014-06-01

    A study of chronic mountain sickness (CMS) with a candidate gene--vascular endothelial growth factor A (VEGFA)--was carried out in a Peruvian population living at high altitude in Cerro de Pasco (4380 m). The study was performed by genotyping of 11 tag SNPs encompassing 2.2 kb of region of VEGFA gene in patients with a diagnosis of CMS (n = 131; 49.1 ± 12.7 years old) and unrelated healthy controls (n = 84; 47.2 ± 13.4 years old). The VEGFA tag SNP rs3025033 was found associated with CMS (p Cerro de Pasco population and HapMap3 population (Fst > 0.36, p < 0.01), suggesting selection is operating on the VEGF gene. Our results suggest that VEGFA is associated with CMS in long-term residents at high altitude in the Peruvian Andes.

  13. Vascular endothelial growth factor A protein level and gene expression in intracranial meningiomas with brain edema

    DEFF Research Database (Denmark)

    Nassehi, Damoun; Dyrbye, Henrik; Andresen, Morten;

    2011-01-01

    Meningiomas are the second most common primary intracranial tumors in adults. Although meningiomas are mostly benign, more than 50% of patients with meningioma develop peritumoral brain edema (PTBE), which may be fatal because of increased intracranial pressure. Vascular endothelial growth factor....... Forty-three patients had primary, solitary, supratentorial meningiomas with PTBE. In these, correlations in PTBE, edema index, VEGF-A protein, VEGF gene expression, capillary length, and tumor water content were investigated. DNA-branched hybridization was used for measuring VEGF gene expression...... in tissue homogenates prepared from frozen tissue samples. The method for VEGF-A analysis resembled an ELISA assay, but was based on chemiluminescence. The edema index was positively correlated to VEGF-A protein (p = 0.014) and VEGF gene expression (p

  14. THE RELATIONSHIP BETWEEN PERITUMORAL BRAIN EDEMA AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN PATIENTS WITH MENINGIOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To determine whether VEGF plays a role in the development of peritumoral brain edema. Methods 50 meningioma patients and their VEGF expression were studied. We took a mono- clonal antibody from mouse to VEGF to stain the tumor cells, the vascular endothelial cells and the interstitial cells. The severity of brain edema was evaluated according to CT or MR scans by the following equation: edema index = Vtumor+edema/Vtumor. The relationship between VEGF expression and edema index was analyzed statisti- cally. Results VEGF was expressed in meningioma tumor cells, which is usually concentrated at the pe- ripheral sites of the tumor. There was a positive linear correlation between the expression and the brain edema index. Conclusion VEGF may play a role in the development of peritumoral brain edema in meningioma patient.

  15. Analysis of active components in Salvia miltiorrhiza injection based on vascular endothelial cell protection.

    Science.gov (United States)

    Shen, Jie; Yang, Kai; Sun, Caihua; Zheng, Minxia

    2014-09-01

    Correlation analysis based on chromatograms and pharmacological activities is essential for understanding the effective components in complex herbal medicines. In this report, HPLC and measurement of antioxidant properties were used to describe the active ingredients of Salvia miltiorrhiza injection (SMI). HPLC results showed that tanshinol, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B, protocatechuic acid and their metabolites in rat serum may contribute to the efficacy of SMI. Assessment of antioxidant properties indicated that differences in the composition of serum powder of SMI caused differences in vascular endothelial cell protection. When bivariate correlation was carried out it was found that salvianolic acid B, tanshinol and protocatechuic aldehyde were active components of SMI because they were correlated to antioxidant properties.

  16. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2.

    Science.gov (United States)

    Spratlin, Jennifer

    2011-04-01

    Angiogenesis, a well-recognized characteristic of malignancy, has been exploited more than any other pathway targeted by biologic anti-neoplastic therapies. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the critical receptor involved in malignant angiogenesis with its activation inducing a number of other cellular modifications resulting in tumor growth and metastases. Ramucirumab (IMC-1121B; ImClone Systems Corporation, Branchburg, NJ) is a fully human monoclonal antibody developed to specifically inhibit VEGFR-2. Ramucirumab is currently being investigated in multiple clinical trials across a variety of tumor types. Herein, angiogenesis inhibition in cancer is reviewed and up-to-date information on the clinical development of ramucirumab is presented.

  17. The Interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Negar Azarpira

    2012-01-01

    Full Text Available We studied the correlation between changes in the serum levels of vascular endothelial growth factor (VEGF and interleukin-6 (IL-6 with complications such as acute graft versus host disease (aGVHD, veno-occlusive disease (VOD or occurrence of infection after hematopoietic stem cell transplantation (HSCT. Serum VEGF and IL-6 levels were sequentially measured by enzyme-linked immunosorbant assay (ELISA in 35 patients who had undergone HSCT. Serum levels of IL-6 in patients with aGVHD were increased in comparison with patients without aGVHD, but the difference was not statistically significant. Serum levels of VEGF were only increased in patients with aGVHD during the early days after transplantation. No signi-ficantly altered levels of IL-6 and VEGF were observed in patients with VOD or sepsis. These results demonstrate that rising levels of VEGF and IL-6 may be good and specific biomarkers for transplant aGVHD.

  18. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Jinah Han

    2015-02-01

    Full Text Available Neural stem cells (NSCs continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs, VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.

  19. Endothelial Progenitor Cells in Peripheral Blood of Cardiac Catheterization Personnel

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    Soheir Korraa1, Tawfik M.S.1, Mohamed Maher 2 and Amr Zaher

    2014-07-01

    Full Text Available Background: The aim of the present study was to evaluate the rejuvenation capacity among cardiac catheterization technicians occupationally exposed to ionizing radiation. Subjects and methods: The individual annual collective dose information was measured by thermoluminscent personal dosimeters (TLD for those technicians and found to be ranging between 2.16 and 8.44 mSv/y. Venous blood samples were obtained from 30 cardiac catheterization technicians exposed to X-ray during fluoroscopy procedures at the National Heart Institute in Embaba. The control group involved 25 persons not exposed to ionizing radiation and not working in hospitals in addition to 20 persons not exposed to ionizing radiation and working in hospitals. Blood samples were assayed for total and differential blood counts, micronucleus formation (FMN plasma stromal derived growth factor-1α (SDF-1 α and cell phenotype of circulating endothelial progenitor cells (EPCs, whose surface markers were identified as the CD34, CD133 and kinase domain receptors (KDR. Results: SDF-1α (2650± 270 vs. 2170 ± 430 pg/ml and FMN (19.9 ± 5.5 vs. 2.8 ± 1.4/1000 cells were significantly higher among cardiac catheterization staff compared to those of the controls respectively. Similarly, EPCs: CD34 (53 ± 3.9 vs. 48 ± 8.5/105 mononuclear cells, CD133 (62.4 ± 4.8 vs. 54.2 ± 10.6 /105 mononuclear cells KDR (52.7 ± 10.6 vs.43.5± 8.2 /105 mononuclear cells were also significantly higher among cardiac catheterization staff compared to the values of controls respectively. Smoking seemed to have a positive effect on the FMN and SDF-1 but had a negative effect on EPCs. It was found that among cardiac catheterization staff, the numbers of circulating progenitor cells had increased and accordingly there was an increased capacity for tissue repair. Conclusion: In conclusion, the present work shows that occupational exposure to radiation, well within permissible levels, leaves a genetic mark on the

  20. Chronic and non-healing wounds: The story of vascular endothelial growth factor.

    Science.gov (United States)

    Zhou, Kehua; Ma, Yan; Brogan, Michael S

    2015-10-01

    The pathophysiology of the chronicity and non-healing status of wounds remains unknown. This paper presents the following hypothesis: abnormal patterns of vascular endothelial growth factor receptors (VEGFRs) are the culprits of wound chronicity and non-healing. More specifically, for patients with poor circulation, the decreased VEGFR-2 level is the cause of poor wound healing; for patients with non-compromised circulation, for example, patients with concurrent chronic wounds and active autoimmune diseases, the increased VEGFR-1 level is related to the non-healing status of wounds. The hypothesis is supported by the following facts. VEGFR-1 is the main contributor for inflammation and VEGFR-2 facilitates angiogenesis; soluble VEGFR-1 (sVEGFR-1) inactivates both VEGFR-1 and VEGFR-2. Patients with auto-immune disease have abnormally increased VEGFR-1 and decreased sVEGFR. Wounds in patients with active autoimmune diseases have poor response to electric stimulation which facilitates chronic wound healing in patients without active autoimmune diseases via increasing vascular endothelial growth factor (VEGF) secretion. Patients with chronic wounds (including diabetic foot ulcers and venous leg ulcers) but no active autoimmune diseases have decreased VEGFR-2 levels. We thus believe that abnormal patterns of VEGFRs are the culprits of wound chronicity and non-healing. For wounds with compromised circulation, VEGFR-2 decrease contributes to its chronicity; whereas for wounds with non-compromised circulation, VEGFR-1 increase is the leading cause of the non-healing status of chronic wounds. Treatments and research in wound care should be tailored to target these changes based on circulation status of wounds. Complete elucidation of changes of VEGFRs in chronic and non-healing wounds will enhance our understandings in tissue healing and thus better our selection of appropriate treatments for chronic and non-healing wounds.

  1. Neuroprotective effect of exogenous vascular endothelial growth factor on rat spinal cord neurons in vitro hypoxia

    Institute of Scientific and Technical Information of China (English)

    DING Xin-min; MAO Bo-yong; JIANG Shu; LI Sheng-fu; DENG Yi-ling

    2005-01-01

    Background Vascular endothelial growth factor (VEGF) is well known as a hypoxia-induced protein. That it markedly increased expression of VEGF and improvement of rat motor function after spinal cord injury suggested that VEGF could play a neuroprotective role in ischaemic tolerance. This study investigated whether vascular endothelial growth factor has direct neuroprotective effects on rat spinal cord neurons. Methods We employed primary cultures of embryonic rat spinal cord neurons, then administrated different concentrations of VEGF164 in the culture medium before hypoxia when the number of neurons was counted and the cell viability was detected by MTT. The neuronal apoptosis and expression of VEGF and its receptor genes were evaluated by terminal deoxynucleotidyl transferase mediated dUTP nick-end labelling (TUNEL) and immunohistochemistry. The VEGFR2/FLK-1 inhibitor, SU1498, was used to confirm whether the neuroprotective effect of VEGF was mediated through VEGFR2/Flk-1 receptors. Result In hypoxic conditions,the number and viability of neurons decreased progressively, while the number of TUNEL-positive cells increased along with the prolongation of hypoxic exposure. When the concentration of VEGF in cell culture medium reached 25 ng/ml, the cell viability increased 11% and neuronal apoptosis reduced to half, this effect was dose dependent and led to an approximately 25% increase in cell viability and about threefold decrease in TUNEL-positive cells at a maximally effective concentration of 100 ng/ml. In normal conditions, VEGF/Flk-1 but not VEGF/Flt-1 gene expressed at a low level: after hypoxia, the expression of VEGF/Flk-1, but not VEGF/Flt-1 was significantly increased. The protective effect of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor, SU1498. Conclusions VEGF has direct neuroprotective effects on rat spinal cord neurons, which may be mediated in vitro through VEGFR2/Flk-1 receptors.

  2. A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors.

    Science.gov (United States)

    Stacker, Steven A; Halford, Michael M; Roufail, Sally; Caesar, Carol; Achen, Marc G

    2016-03-15

    The analysis of receptor tyrosine kinases and their interacting ligands involved in vascular biology is often challenging due to the constitutive expression of families of related receptors, a broad range of related ligands and the difficulty of dealing with primary cultures of specialized endothelial cells. Here we describe a bioassay for the detection of ligands to the vascular endothelial growth factor receptor-2 (VEGFR-2), a key transducer of signals that promote angiogenesis and lymphangiogenesis. A cDNA encoding a fusion of the extracellular (ligand-binding) region of VEGFR-2 with the transmembrane and cytoplasmic regions of the erythropoietin receptor (EpoR) is expressed in the factor-dependent cell line Ba/F3. This cell line grows in the presence of interleukin-3 (IL-3) and withdrawal of this factor results in death of the cells within 24 hr. Expression of the VEGFR-2/EpoR receptor fusion provides an alternative mechanism to promote survival and potentially proliferation of stably transfected Ba/F3 cells in the presence of a ligand capable of binding and cross-linking the extracellular portion of the fusion protein (i.e., one that can cross-link the VEGFR-2 extracellular region). The assay can be performed in two ways: a semi-quantitative approach in which small volumes of ligand and cells permit a rapid result in 24 hr, and a quantitative approach involving surrogate markers of a viable cell number. The assay is relatively easy to perform, is highly responsive to known VEGFR-2 ligands and can accommodate extracellular inhibitors of VEGFR-2 signaling such as monoclonal antibodies to the receptor or ligands, and soluble ligand traps.

  3. Inhibition of tubulointerstitial fibrosis by pentoxifylline is associated with improvement of vascular endothelial growth factor expression

    Institute of Scientific and Technical Information of China (English)

    Qiu-gen ZHOU; Fa-lei ZHENG; Fan-fan HOU

    2009-01-01

    Aim: Recent information indicates that pentoxifylline (PTX) has the ability to suppress inflammation and profibrotic cell proliferation. In this study, we investigated the effect of PTX on tubulointerstitial fibrosis and the expression of vascular endothelial growth factor (VEGF) in a rat model of obstructive nephropathy. Methods: Wistar rats with left ureteral ligation were divided into control and PTX-treated groups. The histopathologic degree of tubulointerstitial fibrosis was scored with PAS and Masson-stained sections. The protein and mRNA for vascular endothelial growth factor (VEGF) were semiquantitatively measured with immunohistochemistry and RT-PCR. The pro-tein for transforming growth factor β1 (TGFβ1) and hypoxia-induced factor 1 alpha (HIF-1α) was determined by Western blot. Results: Compared with the control group, PTX treatment reduced fibrosis scores at d 7 and d 14 (P<0.05). The reduction was accompanied by inhibited expression of transforming growth factor-beta 1 (TGFβ1), a key cytokine in tubulointerstitial fibrogenesis (P<0.01). Meanwhile, VEGF protein and mRNA in the kidney were increased in the PTX-treated group com-pared with the control group (P<0.01). PTX up-regulated expression of VEGF mRNA in a dose- and time-dependent man-ner in cultured HK-2 cells (P<0.01). However, expression of HIF-1α (a key transcription factor for VEGF gene expression) was unchanged by PTX treatment. PTX prolonged the half-life of VEGF mRNA by a 1.07-fold increase. Conclusions: PTX inhibited tubulointerstitial fibrosis in a rat model of obstructive nephropathy while preventing loss of VEGF. PTX up-regulated expression of VEGF mRNA through stabilization of its mRNA in cultured renal tubular epithelial cells.

  4. Effects of black raspberry on lipid profiles and vascular endothelial function in patients with metabolic syndrome.

    Science.gov (United States)

    Jeong, Han Saem; Hong, Soon Jun; Lee, Tae-Bum; Kwon, Ji-Wung; Jeong, Jong Tae; Joo, Hyung Joon; Park, Jae Hyoung; Ahn, Chul-Min; Yu, Cheol Woong; Lim, Do-Sun

    2014-10-01

    Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects. However, short-term effects of black raspberry on lipid profiles and vascular endothelial function have not been investigated in patients with metabolic syndrome. Patients with metabolic syndrome (n = 77) were prospectively randomized into a group with black raspberry (n = 39, 750 mg/day) and a placebo group (n = 38) during a 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD), and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, and sVCAM-1 were measured at the baseline and at the 12-week follow-up. Decreases from the baseline in the total cholesterol level (-22.8 ± 30.4 mg/dL vs. -1.9 ± 31.8 mg/dL, p raspberry than in the placebo group. Increases in baFMD at the 12-week follow-up were significantly greater in the group with black raspberry than in the placebo group (0.33 ± 0.44 mm vs. 0.10 ± 0.35 mm, p raspberry. The use of black raspberry significantly decreased serum total cholesterol level and inflammatory cytokines, thereby improving vascular endothelial function in patients with metabolic syndrome during the 12-week follow-up.

  5. Gelatinases, endonuclease and Vascular Endothelial Growth Factor during development and regression of swine luteal tissue

    Directory of Open Access Journals (Sweden)

    Bacci Maria

    2006-11-01

    Full Text Available Abstract Background The development and regression of corpus luteum (CL is characterized by an intense angiogenesis and angioregression accompanied by luteal tissue and extracellular matrix (ECM remodelling. Vascular Endothelial Growth Factor (VEGF is the main regulator of angiogenesis, promoting endothelial cell mitosis and differentiation. After the formation of neovascular tubes, the remodelling of ECM is essential for the correct development of CL, particularly by the action of specific class of proteolytic enzymes known as matrix metalloproteinases (MMPs. During luteal regression, characterized by an apoptotic process and successively by an intense ECM and luteal degradation, the activation of Ca++/Mg++-dependent endonucleases and MMPs activity are required. The levels of expression and activity of VEGF, MMP-2 and -9, and Ca++/Mg++-dependent endonucleases throughout the oestrous cycle and at pregnancy were analyzed. Results Different patterns of VEGF, MMPs and Ca++/Mg++-dependent endonuclease were observed in swine CL during different luteal phases and at pregnancy. Immediately after ovulation, the highest levels of VEGF mRNA/protein and MMP-9 activity were detected. On days 5–14 after ovulation, VEGF expression and MMP-2 and -9 activities are at basal levels, while Ca++/Mg++-dependent endonuclease levels increased significantly in relation to day 1. Only at luteolysis (day 17, Ca++/Mg++-dependent endonuclease and MMP-2 spontaneous activity increased significantly. At pregnancy, high levels of MMP-9 and VEGF were observed. Conclusion Our findings, obtained from a precisely controlled in vivo model of CL development and regression, allow us to determine relationships among VEGF, MMPs and endonucleases during angiogenesis and angioregression. Thus, CL provides a very interesting model for studying factors involved in vascular remodelling.

  6. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

    Science.gov (United States)

    Li, Ping; Liu, Huaipu; Sun, Peng; Wang, Xiaoyu; Wang, Chen; Wang, Ling; Wang, Tinghuai

    2016-02-01

    Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

  7. A model for studying the effect of shear stress on interactions between vascular endothelial cells and smooth muscle cells.

    Science.gov (United States)

    Chiu, Jeng-Jiann; Chen, Li-Jing; Chen, Cheng-Nan; Lee, Pei-Ling; Lee, Chih-I

    2004-04-01

    Vascular endothelial cells (ECs) are constantly subjected to blood flow-induced shear stress and the influences of neighboring smooth muscle cells (SMCs). In the present study, a coculture flow system was developed to study the effect of shear stress on EC-SMC interactions. ECs and SMCs were separated by a porous membrane with only the EC side subjected to the flow condition. When ECs were exposed to a shear stress of 12 dynes/cm2 for 24 h, the cocultured SMCs tended to orient perpendicularly to the flow direction. This perpendicular orientation of the cocultured SMCs to flow direction was not observed when ECs were exposed to a shear stress of 2 dynes/cm2. Under the static condition, long and parallel actin bundles were observed in the central regions of the cocultured SMCs, whereas the actin filaments localized mainly at the periphery of the cocultured ECs. After 24 h of flow application, the cocultured ECs displayed very long, well-organized, parallel actin stress fibers aligned with the flow direction in the central regions of the cells. Immunostaining of platelet endothelial cell adhesion molecule-1 confirmed the elongation and alignment of the cocultured ECs with the flow direction. Coculture with SMCs under static condition induced EC gene expressions of growth-related oncogene-alpha and monocyte chemotactic protein-1, and shear stress was found to abolish these SMC-induced gene expressions. Our results suggest that shear stress may serve as a down-regulator for the pathophysiologically relevant gene expression in ECs cocultured with SMCs.

  8. Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy.

    Directory of Open Access Journals (Sweden)

    Feilim Mac Gabhann

    2006-09-01

    Full Text Available Members of the vascular endothelial growth factor (VEGF family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in

  9. Bisphenol A Disrupts Transcription and Decreases Viability in Aging Vascular Endothelial Cells

    Science.gov (United States)

    Ribeiro-Varandas, Edna; Pereira, H. Sofia; Monteiro, Sara; Neves, Elsa; Brito, Luísa; Boavida Ferreira, Ricardo; Viegas, Wanda; Delgado, Margarida

    2014-01-01

    Bisphenol A (BPA) is a widely utilized endocrine disruptor capable of mimicking endogenous hormones, employed in the manufacture of numerous consumer products, thereby interfering with physiological cellular functions. Recent research has shown that BPA alters epigenetic cellular mechanisms in mammals and may be correlated to enhanced cellular senescence. Here, the effects of BPA at 10 ng/mL and 1 µg/mL, concentrations found in human samples, were analyzed on HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) transcriptional analysis of the Long Interspersed Element-1 (LINE-1) retroelement showed that BPA induces global transcription deregulation in both cell lines, although with more pronounced effects in HUVEC cells. Whereas there was an increase in global transcription in HT29 exclusively after 24 h of exposure, this chemical had prolonged effects on HUVEC. Immunoblotting revealed that this was not accompanied by alterations in the overall content of H3K9me2 and H3K4me3 epigenetic marks. Importantly, cell viability assays and transcriptional analysis indicated that prolonged BPA exposure affects aging processes in senescent HUVEC. To our knowledge this is the first report that BPA interferes with senescence in primary vascular endothelial cells, therefore, suggesting its association to the etiology of age-related human pathologies, such as atherosclerosis. PMID:25207595

  10. Platelet and endothelial adhesion on fluorosurfactant polymers designed for vascular graft modification.

    Science.gov (United States)

    Tang, Chad; Kligman, Faina; Larsen, Coby C; Kottke-Marchant, Kandice; Marchant, Roger E

    2009-02-01

    A prominent failure mechanism of small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts is platelet-mediated thrombosis. We have designed a surface modification for ePTFE consisting of a self-assembling fluorosurfactant polymer (FSP) bearing biologically active ligands, including adhesive peptides and polysaccharide moieties. The goal of this biomimetic construct is to improve graft hemocompatibility by promoting rapid surface endothelialization, whereas minimizing platelet adhesion. Here we present a direct comparison of platelet and endothelial cell (EC) adhesion to FSPs containing one of three cell-adhesion peptides: cyclic Arg-Gly-Asp-D-Phe-Glu (cRGD), cyclic *Cys-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys* (cRRE, *denotes disulfide bond cyclization), linear Gly-Arg-Gly-Asp-Ser-Pro-Ala (RGD), or a polysaccharide moiety: oligomaltose (M-7), later designed to prevent nonspecific protein adhesion. Measurements of soluble peptide-integrin binding indicated that cRRE exhibits very low affinity for the alpha(IIb)beta(3) platelet fibrinogen receptor. Static and dynamic adhesion of washed, activated platelets on FSP-modified surfaces revealed that M-7 and cRRE promote significantly less platelet adhesion compared to RGD and cRGD FSPs, whereas EC adhesion was similar on all peptide FSPs and minimal on M-7 FSP. These results illustrate the potential for ligands presented in a FSP surface modification to selectively adhere ECs with limited platelet attachment.

  11. Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity.

    Science.gov (United States)

    Puhlmann, Markus; Weinreich, David M; Farma, Jeffrey M; Carroll, Nancy M; Turner, Ewa M; Alexander, H Richard

    2005-09-30

    IL-1beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

  12. Interleukin-1β induced vascular permeability is dependent on induction of endothelial Tissue Factor (TF activity

    Directory of Open Access Journals (Sweden)

    Turner Ewa M

    2005-09-01

    Full Text Available Abstract IL-1β is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1β are mediated through induction of tissue factor (TF but its alterations on vascular permeability are not well characterized. We found that IL-1β induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs under routine culture conditions. However, IL-1β caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1β induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

  13. [Study on FAK regulation of migration of vascular endothelial cells depending upon focal adhesion proteins].

    Science.gov (United States)

    Gao, Min; Liu, Xiaoheng; Sun, Heng; Ren, Hongyi; Wang, Lijuan; Shen, Yang

    2013-06-01

    Tumor angiogenesis induced by vascular endothelial cells (VECs) migration is a necessary condition for tumor growth and metastasis. The purpose of this study is to investigate the effect of focal adhesion kinase (FAK) inhibitor (50nmol/mL) on the adhesion and migration of endothelial cells(ECs) and the expression of focal adhesion proteins vinculin, talin and paxillin. Scratch wound migration assay was performed to examine the effect of FAK inhibitor with 50nmol/mL on ECs migration at 0, 5, 10, 30, 60 and 120min, respectively. And immunofluorescence analysis was performed to detect the expression of F-actin in ECs treated with FAK inhibitor within 2h. Western blot was carried out to determine the effect of FAK inhibitor on expression of vinculin, talin and paxillin proteins. The results showed that the migration distance and the expression of F-actin in ECs treated with FAK inhibitor decreased significantly compared with that of the controls, and the level of vinculin showed no significant difference with increasing of treated time of FAK inhibitor. However, the talin and paxillin showed an identical decreasing tendency in 5-10min, but slowly going up in 30min and then after subsequently decreasing. The results of this study proved that blocking phosphorylation of FAK could inhibit VECs adhesion and migration by downregulating focal adhesion proteins so that it may inhibit tumor angiogenesis. This may provide a new approach for tumor therapy.

  14. (-)-Epigallocatechin gallate inhibits TNF-α-induced PAI-1 production in vascular endothelial cells.

    Science.gov (United States)

    Cao, Yanli; Wang, Difei; Wang, Xiaoli; Zhang, Jin; Shan, Zhongyan; Teng, Weiping

    2013-11-01

    : (-)-Epigallocatechin gallate (EGCG), the major catechin derived from green tea, reduces the incidence of cardiovascular diseases such as atherosclerosis. Plasminogen activator inhibitor-1 (PAI-1) accelerates thrombus formation upon ruptured atherosclerotic plaques. However, it is not known whether or not EGCG inhibits PAI-1 production induced by tumor necrosis factor-α (TNF-α) in endothelial cells. This study tested the hypothesis that EGCG might have an inhibitory effect on PAI-1 production induced by TNF-α. Human umbilical vein endothelial cells were cultured and incubated with TNF-α and/or EGCG. The expression of p-extracellular regulated protein kinases (p-ERK1/2) and tumor necrosis factor receptor (TNFR1) protein was quantified by Western blotting, and PAI-1 levels were measured by enzyme-linked immunosorbent assay. The results showed that TNF-α increased PAI-1 production in both a dose-dependent and time-dependent manner, and EGCG prevented TNF-α-mediated PAI-1 production and reduced phosphorylation of ERK1/2. The ERK1/2 inhibitor, PD98059 (20 μmol/L), downregulated TNF-α-induced PAI-1 expression 57.69 ± 2.46% (P TNF-α stimulation resulted in a significant decrease in TNFR1, an effect that was abolished by pretreatment with EGCG. These results suggest that EGCG could provide vascular benefits in inflammatory cardiovascular diseases such as decreased thrombus formation associated with ruptured atherosclerotic plaques.

  15. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Lamy, Sylvie, E-mail: lamy.sylvie@uqam.ca; Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R.

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention. - Highlights: • We investigated five compounds contained in extra virgin olive oil on angiogenesis. • Hydroxytyrosol, taxifolin and oleic acid are the best angiogenesis inhibitors. • Olive oil compounds affect endothelial cell functions essential for

  16. Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor.

    Science.gov (United States)

    Tsuji, Masako; Murota, Se-itsu; Morita, Ikuo

    2003-05-01

    It is generally accepted that n-3 polyunsaturated fatty acids have beneficial effects on vascular homeostasis. Among the several functions of endothelial cells, angiogenesis contributes to tumor growth, inflammation, and microangiopathy. We have already demonstrated that eicosapentaenoic acid (EPA, 20:5, n-3) suppressed angiogenesis. In this paper, we examined the effect of docosapentaenoic acid (DPA, 22:5, n-3), an elongated metabolite of EPA, on tube-forming activity in bovine aortic endothelial cells (BAE cells) incubated between type I collagen gels. The pretreatment of BAE cells with DPA suppressed tube-forming activity induced by vascular endothelial growth factor (VEGF). The effect of DPA was stronger than those of EPA and docosahexaenoic acid (22:6, n-3). The migrating activity of endothelial cells stimulated with VEGF was also suppressed by DPA pretreatment. The treatment of BAE cells with DPA caused the suppression of VEGF receptor-2 (VEGFR-2, the kinase insert domain-containing receptor, KDR) expression in both plastic dish and collagen gel cultures. These data indicate that DPA has a potent inhibitory effect on angiogenesis through the suppression of VEGFR-2 expression.

  17. Immortalized endothelial cell lines for in vitro blood-brain barrier models: A systematic review.

    Science.gov (United States)

    Rahman, Nurul Adhwa; Rasil, Alifah Nur'ain Haji Mat; Meyding-Lamade, Uta; Craemer, Eva Maria; Diah, Suwarni; Tuah, Ani Afiqah; Muharram, Siti Hanna

    2016-07-01

    Endothelial cells play the most important role in construction of the blood-brain barrier. Many studies have opted to use commercially available, easily transfected or immortalized endothelial cell lines as in vitro blood-brain barrier models. Numerous endothelial cell lines are available, but we do not currently have strong evidence for which cell lines are optimal for establishment of such models. This review aimed to investigate the application of immortalized endothelial cell lines as in vitro blood-brain barrier models. The databases used for this review were PubMed, OVID MEDLINE, ProQuest, ScienceDirect, and SpringerLink. A narrative systematic review was conducted and identified 155 studies. As a result, 36 immortalized endothelial cell lines of human, mouse, rat, porcine and bovine origins were found for the establishment of in vitro blood-brain barrier and brain endothelium models. This review provides a summary of immortalized endothelial cell lines as a guideline for future studies and improvements in the establishment of in vitro blood-brain barrier models. It is important to establish a good and reproducible model that has the potential for multiple applications, in particular a model of such a complex compartment such as the blood-brain barrier.

  18. Antibodies against AT1 receptors are associated with vascular endothelial and smooth muscle function impairment: protective effects of hydroxysafflor yellow A.

    Directory of Open Access Journals (Sweden)

    Zhu Jin

    Full Text Available Ample evidence has shown that autoantibodies against AT1 receptors (AT1-AA are closely associated with human cardiovascular disease. The aim of this study was to investigate mechanisms underlying AT1-AA-induced vascular structural and functional impairments in the formation of hypertension, and explore ways for preventive treatment. We used synthetic peptide corresponding to the sequence of the second extracellular loop of the AT1 receptor (165-191 to immunize rats and establish an active immunization model. Part of the model received preventive therapy by losartan (20 mg/kg/day and hyroxysafflor yellow A (HSYA (10 mg/kg/day. The result show that systolic blood pressure (SBP and heart rate (HR of immunized rats was significantly higher, and closely correlated with the plasma AT1-Ab titer. The systolic response of thoracic aortic was increased, but diastolic effects were attenuated markedly. Histological observation showed that the thoracic aortic endothelium of the immunized rats became thinner or ruptured, inflammatory cell infiltration, medial smooth muscle cell proliferation and migration, the vascular wall became thicker. There was no significant difference in serum antibody titer between losartan and HSYA groups and the immunized group. The vascular structure and function were reversed, and plasma biochemical parameters were also improved significantly in the two treatment groups. These results suggest that AT1-Ab could induce injury to vascular endothelial cells, and proliferation of smooth muscle cells. These changes were involved in the formation of hypertension. Treatment with AT1 receptor antagonists and anti oxidative therapy could block the pathogenic effect of AT1-Ab on vascular endothelial and smooth muscle cells.

  19. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress.

    Science.gov (United States)

    Hou, Jinling; Wang, Shaohui; Shang, Yan Chen; Chong, Zhao Zhong; Maiese, Kenneth

    2011-08-01

    Given the cytoprotective ability of erythropoietin (EPO) in cerebral microvascular endothelial cells (ECs) and the invaluable role of ECs in the central nervous system, it is imperative to elucidate the cellular pathways for EPO to protect ECs against brain injury. Here we illustrate that EPO relies upon the modulation of SIRT1 (silent mating type information regulator 2 homolog 1) in cerebral microvascular ECs to foster cytoprotection during oxygen-glucose deprivation (OGD). SIRT1 activation which results in the inhibition of apoptotic early membrane phosphatidylserine (PS) externalization and subsequent DNA degradation during OGD becomes a necessary component for EPO protection in ECs, since inhibition of SIRT1 activity or diminishing its expression by gene silencing abrogates cell survival supported by EPO during OGD. Furthermore, EPO promotes the subcellular trafficking of SIRT1 to the nucleus which is necessary for EPO to foster vascular protection. EPO through SIRT1 averts apoptosis through activation of protein kinase B (Akt1) and the phosphorylation and cytoplasmic retention of the forkhead transcription factor FoxO3a. SIRT1 through EPO activation also utilizes mitochondrial pathways to prevent mitochondrial depolarization, cytochrome c release, and Bad, caspase 1, and caspase 3 activation. Our work identifies novel pathways for EPO in the vascular system that can govern the activity of SIRT1 to prevent apoptotic injury through Akt1, FoxO3a phosphorylation and trafficking, mitochondrial membrane permeability, Bad activation, and caspase 1 and 3 activities in ECs during oxidant stress.

  20. Effect of Ginkgo Leaf Extract on Vascular Endothelial Function in Patients with Early Stage Diabetic Nephropathy

    Institute of Scientific and Technical Information of China (English)

    LI Xu-sheng; ZHENG Wei-ying; LOU Shi-xian; LU Xiao-wen; YE Shang-he

    2009-01-01

    Objective: To explore the effect of ginkgo leaf extract (GLE) on vascular endothelial function (VEF) in patients with early stage diabetic nephropathy (DN). Methods: Sixty-four patients were randomized equally by a randomzing digital table into two groups, the treated group and the control group. They were all treated for 8 weeks with conventional therapy for diabetes, but GLE tablets were given to the treated group additionally. Changes in VEF were estimated before and after treatment by ultrasonic examination of the brachial artery. In the meantime, changes in plasma levels of the von Willebrand factor (vWF), nitric oxide (NO) and endothelin-1 (ET-1) were observed as well. Results: The brachial arterial endothelium dependent dilating function in the treated group increased from 4.91±2.31% before treatment to 6.78±3.89% after treatment (P0.05). Conclusion: GLE could decrease the plasma level of vWF, raise the plasma NO level and improve the endothelium dependent vascular dilating function in DN patients.

  1. Impact of Enzymatic Degradation of the Endothelial Glycocalyx on Vascular Permeability in an Awake Hamster Model

    Directory of Open Access Journals (Sweden)

    S. A. Landsverk

    2012-01-01

    Full Text Available Background. The inside of the endothelium is covered by a glycocalyx layer, and enzymatic degradation of this layer induces vascular leakage ex vivo. We hypothesized that enzymatic degrading of the glycocalyx in an in vivo, whole body model, would induce plasma leakage and affect the microcirculation. Methods. Golden Syrian hamsters were divided into an enzyme (hyaluronidase and a control group. Mean arterial pressure (MAP, heart rate (HR, hematocrit (Hct, base excess (BE, and plasma volume were obtained before, 45 and 120 min after enzyme/saline treatment. Plasma volume was evaluated by the distribution volume of indocyanine green and the microcirculation by functional capillary density (FCD. The enzymatic effect was determined by measuring plasma levels of hyaluronan (HA. Results. There were no differences in MAP, HR, Hct, and BE between the two groups. Enzyme treatment did not induce changes in plasma volume but reduced FCD. There was a 50–100-fold increase in plasma HA, but no relationship was found between HA levels and plasma volume or FCD. Conclusion. Vascular leakage was not confirmed in an in vivo, whole body model after degradation of the endothelial glycocalyx. The microcirculation was affected, but no relationship between plasma levels of HA and FCD was seen.

  2. Gliomas and the vascular fragility of the blood brain barrier

    Science.gov (United States)

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  3. Ameliorative effect of combination of benfotiamine and fenofibrate in diabetes-induced vascular endothelial dysfunction and nephropathy in the rat.

    Science.gov (United States)

    Balakumar, Pitchai; Chakkarwar, Vishal Arvind; Singh, Manjeet

    2009-01-01

    The study has been designed to investigate the effect of benfotiamine and fenofibrate in diabetes-induced experimental vascular endothelial dysfunction (VED) and nephropathy. The single administration of streptozotocin (STZ) (50 mg/kg, i.p.) produced diabetes, which was noted to develop VED and nephropathy in 8 weeks. The diabetes produced VED by attenuating acetylcholine-induced endothelium dependent relaxation, impairing the integrity of vascular endothelium, decreasing serum nitrite/nitrate concentration and increasing serum TBARS and aortic superoxide anion generation. Further, diabetes altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. The nephropathy was noted to be developed in the diabetic rat that was assessed in terms of increase in serum creatinine, blood urea, proteinuria, and glomerular damage. The benfotiamine (70 mg/kg, p.o.) and fenofibrate (32 mg/kg, p.o.) or lisinopril (1 mg/kg, p.o., a standard agent) treatments were started in diabetic rats after 1 week of STZ administration and continued for 7 weeks. The treatment with benfotiamine and fenofibrate either alone or in combination attenuated diabetes-induced VED and nephropathy. In addition, the combination of benfotiamine and fenofibrate was noted to be more effective in attenuating the diabetes-induced VED and nephropathy when compared to treatment with either drug alone or lisinopril. Treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, whereas benfotiamine treatment has no effect on lipid alteration in diabetic rats. It may be concluded that diabetes-induced oxidative stress, lipids alteration, and consequent development of VED may be responsible for the induction of nephropathy in diabetic rats. Concurrent administration of benfotiamine and fenofibrate may provide synergistic benefits in preventing the development of diabetes-induced nephropathy by reducing the oxidative stress and lipid

  4. In Vitro Model of Physiological and Pathological Blood Flow with Application to Investigations of Vascular Cell Remodeling.

    Science.gov (United States)

    Elliott, Winston; Scott-Drechsel, Devon; Tan, Wei

    2015-11-03

    Vascular disease is a common cause of death within the United States. Herein, we present a method to examine the contribution of flow dynamics towards vascular disease pathologies. Unhealthy arteries often present with wall stiffening, scarring, or partial stenosis which may all affect fluid flow rates, and the magnitude of pulsatile flow, or pulsatility index. Replication of various flow conditions is the result of tuning a flow pressure damping chamber downstream of a blood pump. Introduction of air within a closed flow system allows for a compressible medium to absorb pulsatile pressure from the pump, and therefore vary the pulsatility index. The method described herein is simply reproduced, with highly controllable input, and easily measurable results. Some limitations are recreation of the complex physiological pulse waveform, which is only approximated by the system. Endothelial cells, smooth muscle cells, and fibroblasts are affected by the blood flow through the artery. The dynamic component of blood flow is determined by the cardiac output and arterial wall compliance. Vascular cell mechano-transduction of flow dynamics may trigger cytokine release and cross-talk between cell types within the artery. Co-culture of vascular cells is a more accurate picture reflecting cell-cell interaction on the blood vessel wall and vascular response to mechanical signaling. Contribution of flow dynamics, including the cell response to the dynamic and mean (or steady) components of flow, is therefore an important metric in determining disease pathology and treatment efficacy. Through introducing an in vitro co-culture model and pressure damping downstream of blood pump which produces simulated cardiac output, various arterial disease pathologies may be investigated.

  5. Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial Nitric Oxide Synthase

    Directory of Open Access Journals (Sweden)

    ML Rossi

    2009-06-01

    Full Text Available Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or fissuring, and the exposure of highly thrombogenic material to blood. It has been demonstrated that the proliferation of vascular smooth muscle cells (VSMCs and impaired bioavailabilty of nitric oxide (NO are among the most important mechanisms involved in the progression of atherosclerosis. It has also been suggested that a NO imbalance in coronary arteries may be involved in myocardial ischemia as a result of vasomotor dysfunction triggering plaque rupture and the thrombotic response. We used 5’ nuclease assays (TaqMan™ PCRs to study gene expression in coronary plaques collected by means of therapeutic directional coronary atherectomy from 15 patients with stable angina (SA and 15 with acute coronary syndromes (ACS without ST elevation. Total RNA was extracted from the 30 plaques and the cDNA was amplified in order to determine endothelial nitric oxide synthase (eNOS gene expression. Analysis of the results showed that the expression of eNOS was significantly higher (p<0.001 in the plaques from the ACS patients. Furthermore, isolated VSMCs from ACS and SA plaques confirmed the above pattern even after 25 plating passages. In situ RT-PCR was also carried out to co-localize the eNOS messengers and the VSMC phenotype.

  6. Modeling of [Formula: see text]-mediated calcium signaling in vascular endothelial cells induced by fluid shear stress and ATP.

    Science.gov (United States)

    Li, Long-Fei; Xiang, Cheng; Qin, Kai-Rong

    2015-10-01

    The calcium signaling plays a vital role in flow-dependent vascular endothelial cell (VEC) physiology. Variations in fluid shear stress and ATP concentration in blood vessels can activate dynamic responses of cytosolic-free [Formula: see text] through various calcium channels on the plasma membrane. In this paper, a novel dynamic model has been proposed for transient receptor potential vanilloid 4 [Formula: see text]-mediated intracellular calcium dynamics in VECs induced by fluid shear stress and ATP. Our model includes [Formula: see text] signaling pathways through P2Y receptors and [Formula: see text] channels (indirect mechanism) and captures the roles of the [Formula: see text] compound channels in VEC [Formula: see text] signaling in response to fluid shear stress (direct mechanism). In particular, it takes into account that the [Formula: see text] compound channels are regulated by intracellular [Formula: see text] and [Formula: see text] concentrations. The simulation studies have demonstrated that the dynamic responses of calcium concentration produced by the proposed model correlate well with the existing experimental observations. We also conclude from the simulation studies that endogenously released ATP may play an insignificant role in the process of intracellular [Formula: see text] response to shear stress.

  7. Magnetic-composite-modified polycrystalline silicon nanowire field-effect transistor for vascular endothelial growth factor detection and cancer diagnosis.

    Science.gov (United States)

    Chen, Hsiao-Chien; Qiu, Jian-Tai; Yang, Fu-Liang; Liu, Yin-Chih; Chen, Min-Cheng; Tsai, Rung-Ywan; Yang, Hung-Wei; Lin, Chia-Yi; Lin, Chu-Chi; Wu, Tzong-Shoon; Tu, Yi-Ming; Xiao, Min-Cong; Ho, Chia-Hua; Huang, Chien-Chao; Lai, Chao-Sung; Hua, Mu-Yi

    2014-10-01

    This study proposes a vascular endothelial growth factor (VEGF) biosensor for diagnosing various stages of cervical carcinoma. In addition, VEGF concentrations at various stages of cancer therapy are determined and compared to data obtained by computed tomography (CT) and cancer antigen 125 (CA-125). The increase in VEGF concentrations during operations offers useful insight into dosage timing during cancer therapy. This biosensor uses Avastin as the biorecognition element for the potential cancer biomarker VEGF and is based on a n-type polycrystalline silicon nanowire field-effect transistor (poly-SiNW-FET). Magnetic nanoparticles with poly[aniline-co-N-(1-one-butyric acid) aniline]-Fe3O4 (SPAnH-Fe3O4) shell-core structures are used as carriers for Avastin loading and provide rapid purification due to their magnetic properties, which prevent the loss of bioactivity; furthermore, the high surface area of these structures increases the quantity of Avastin immobilized. Average concentrations in human blood for species that interfere with detection specificity are also evaluated. The detection range of the biosensor for serum samples covers the results expected from both healthy individuals and cancer patients.

  8. Myeloid-Derived Vascular Endothelial Growth Factor and Hypoxia-Inducible Factor Are Dispensable for Ocular Neovascularization—Brief Report

    Science.gov (United States)

    Liyanage, Sidath E.; Fantin, Alessandro; Villacampa, Pilar; Lange, Clemens A.; Denti, Laura; Cristante, Enrico; Smith, Alexander J.; Ali, Robin R.; Luhmann, Ulrich F.

    2016-01-01

    Objective— Ocular neovascularization (ONV) is a pathological feature of sight-threatening human diseases, such as diabetic retinopathy and age-related macular degeneration. Macrophage depletion in mouse models of ONV reduces the formation of pathological blood vessels, and myeloid cells are widely considered an important source of the vascular endothelial growth factor A (VEGF). However, the importance of VEGF or its upstream regulators hypoxia-inducible factor-1α (HIF1α) and hypoxia-inducible factor-2α (HIF2α) as myeloid-derived regulators of ONV remains to be determined. Approach and Results— We used 2 mouse models of ONV, choroidal neovascularization and oxygen-induced retinopathy, to show that Vegfa is highly expressed by several cell types, but not myeloid cells during ONV. Moreover, myeloid-specific VEGF ablation did not reduce total ocular VEGF during choroidal neovascularization or oxygen-induced retinopathy. In agreement, the conditional inactivation of Vegfa, Hif1a, or Epas1 in recruited and resident myeloid cells that accumulated at sites of neovascularization did not significantly reduce choroidal neovascularization or oxygen-induced retinopathy. Conclusions— The finding that myeloid cells are not a significant local source of VEGF in these rodent models of ONV suggests that myeloid function in neovascular eye disease differs from skin wound healing and other neovascular pathologies. PMID:26603154

  9. Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase.

    Science.gov (United States)

    Longo, Monica; Jain, Venu; Vedernikov, Yuri P; Bukowski, Radek; Garfield, Robert E; Hankins, Gary D; Anderson, Garland D; Saade, George R

    2005-05-01

    Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3-/-KO, where KO is knockout) and wild-type (WT) mice (NOS3+/+WT) were crossbred to produce homozygous NOS3-/-KO, maternally derived heterozygous (NOS3+/-mat, mother with NOS3 deficiency), paternally derived heterozygous (NOS3+/-pat, normal mother), and NOS3+/+WT litters. Number of fetuses per litter was smaller in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Adult female mice from these litters (7-8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Acetylcholine caused vasorelaxation in NOS3+/-pat and NOS3+/+WT and contraction in NOS3-/-KO and NOS3+/-mat mice. Responses to phenylephrine and Ca2+ were increased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Relaxation to isoproterenol was decreased in NOS3-/-KO and NOS3+/-mat vs. NOS3+/-pat and NOS3+/+WT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/-mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3+/-pat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.

  10. Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice

    Institute of Scientific and Technical Information of China (English)

    Volker Schmitz; Miroslaw Kornek; Tobias Hilbert; Christian Dzienisowicz; Esther Raskopf; Christian Rabe; Tilman Sauerbruch; Cheng Qian; Wolfgang H Caselmann

    2005-01-01

    AIM: Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor (VEGF) via stimulating endothelial cell proliferation, migration, and survival.Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities.Here, we tested a recombinant adenovirus, AdsFlt1-3,that encodes an antagonistically acting fragment of the VEGF receptor 1 (Flt-1), for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.METHODS: Murine colorectal carcinoma cells (CT26) were inoculated subcutaneously into Balb/c mice forin vivo studies. Tumor size and survival were determined. 293cell line was used for propagation of the adenoviral vectors.Human lung cancer line 4549 and human umbilical vein endothelial cells were transfected forin vitro experiments.RESULTS: Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 (5×109 PFU/animal) was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation. In spite of these antitumoral effects, the survival time was not improved.According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.CONCLUSION: In this study we confirmed the value of a systemic administration of AdsFlt1-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.

  11. Salvianolic acid B inhibits platelets-mediated inflammatory response in vascular endothelial cells.

    Science.gov (United States)

    Xu, Shixin; Zhong, Aiqin; Bu, Xiaokun; Ma, Huining; Li, Wei; Xu, Xiaomin; Zhang, Junping

    2015-01-01

    Salvianolic acid B (SAB) is a hydrophilic component isolated from the Chinese herb Salviae miltiorrhizae, which has been used clinically for the treatment of ischemic cardiovascular and cerebrovascular diseases. Platelets-mediated vascular inflammatory response contributes to the initiation and progression of atherosclerosis. In this paper, we focus on the modulating effects of SAB on the inflammatory reaction of endothelial cells triggered by activated platelets. Human umbilical vein endothelial cells (EA.hy926) were pretreated with SAB followed by co-culture with ADP-activated platelets. Adhesion of platelets to endothelial cells was observed by amorphological method. The activation of nuclear factor-kappa B was evaluated by NF-κB p65 nuclear translocation and the protein phosphorylation. A determination of the pro-inflammatory mediators (ICAM-1, IL-1β, IL-6, IL-8, MCP-1) mRNA and protein were also conducted. In addition, the inhibitory effects of SAB on platelets activation were also evaluated using a platelet aggregation assay and assessing the release level of soluble P-selectin. The results showed that SAB dose-dependently inhibited ADP- or α-thrombin-induced human platelets aggregation in platelet rich plasma (PRP) samples, and significantly decreased soluble P-selectin release from both agonists stimulated washed platelets. It was also found that pre-treatment with SAB reduced adhesion of ADP-activated platelets to EA.hy926 cells and inhibited NF-κB activation. In addition, SAB significantly suppressed pro-inflammatory mediators mRNA and protein in EA.hy926 cells in a dose-dependent manner. These results indicated that, in addition to its inhibitory effects on platelets activation, SAB was able to attenuate platelets-mediated inflammatory responses in endothelial cells even if the platelets had already been activated. This anti-inflammatory effect was related to the inhibition of NF-κB activation. Our findings suggest that SAB may be a potential

  12. Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation.

    Science.gov (United States)

    Davel, Ana Paula C; Kawamoto, Elisa Mitiko; Scavone, Cristoforo; Vassallo, Dalton V; Rossoni, Luciana V

    2006-07-01

    1. The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg-1 day-1, s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2. Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of Nomega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 microM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3. Neither losartan (10 microM) nor indomethacin (10 microM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml-1) and L-arginine (5 mM), but neither catalase (300 U ml-1) nor apocynin (100 microM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4. In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which

  13. Blood flow interplays with elastin: collagen and MMP: TIMP ratios to maintain healthy vascular structure and function

    Directory of Open Access Journals (Sweden)

    Poulami Basu

    2010-03-01

    thickness and elastin:collagen ratios had a threshold in blood flow in the range 0.6–2.5 mL/min, which increased robustly if blood flow increased to 2.7 mL/min. This pattern was inverted by the total MMP:TIMP ratio. We conclude that vascular remodeling is a function of rate of blood flow, which would in turn be determined by the amounts of MMPs and their inhibitors present. The study combined the endothelial and dynamic (blood flow/pressure components that affect medial thickness and elastin: collagen ratios.Keywords: vascular remodeling, atherosclerosis, passive stretch-tension relationship

  14. A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

    DEFF Research Database (Denmark)

    Fens, Marcel H A M; van Wijk, Richard; Andringa, Grietje

    2012-01-01

    Background Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells gener...... cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.......Background Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells...... generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and αv-integrin. Phagocytosis via the phosphatidylserine...

  15. Impaired blood rheology is associated with endothelial dysfunction in patients with coronary risk factors.

    Science.gov (United States)

    Yagi, Hideki; Sumino, Hiroyuki; Aoki, Tomoyuki; Tsunekawa, Katsuhiko; Araki, Osamu; Kimura, Takao; Nara, Makoto; Ogiwara, Takayuki; Murakami, Masami

    2016-01-01

    To investigate the relationship between blood rheology and endothelial function in patients with coronary risk factors, brachial arterial flow-mediated vasodilatation (FMD), an index of endothelial function and blood passage time (BPT), an index of blood rheology, and fasting blood cell count, glucose metabolism, and plasma fibrinogen, lipid, C-reactive protein, and whole blood viscosity levels were measured in 95 patients with coronary risk factors and 37 healthy controls. Brachial arterial FMD after reactive hyperemia was assessed by ultrasonography. BPT was assessed using the microchannel method. In healthy controls, BPT significantly correlated with FMD (r = - 0.325, p rheology using the microchannel method may be useful in evaluating brachial arterial endothelial function as a marker of atherosclerosis in these patients.

  16. The Soluble Epoxide Hydrolase Inhibitor AR9281 Decreases Blood Pressure, Ameliorates Renal Injury and Improves Vascular Function in Hypertension

    Directory of Open Access Journals (Sweden)

    Sean Shaw

    2009-12-01

    Full Text Available Soluble epoxide hydrolase inhibitors (sEHIs are demonstrating promise as potential pharmaceutical agents for the t