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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells constitute an essential integrator of factors that effect blood vessel remodeling induced by chronic hypoxia. We hypothesized that vascular endothelial growth factor (VEGF) may participate in the lung response to acute and to chronic hypoxia. We found that ex vivo perfusion of isolated lungs under hypoxic conditions (when compared with normoxia) caused an increase in lung tissue mRNA of VEGF and of the VEGF receptors KDR/Flk and Flt. Chronic hypobaric hypoxia also increased lung tissue mRNA levels of VEGF, KDR/Flk, and Flt and the amount of VEGF protein. In situ hybridization studies demonstrated increased VEGF and KDR/flk hybridization signals in lungs from chronically hypoxic rats. Since endotoxin treatment of rats decreased lung VEGF mRNA, we postulated that nitric oxide (NO) or an NO-related metabolite might be involved in lung VEGF gene expression. Indeed, sodium nitroprusside, a NO donor, decreased and L-NAME (N-nitro-L-arginine methyl ester), an inhibitor of NO-synthesis, increased both VEGF and VEGF receptor transcripts. We conclude that VEGF in the isolated perfused lung acts as an early gene in response to hypoxia and that lung VEGF and VEGF receptor mRNA levels are influenced by hypoxia and NO-dependent mechanisms.
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PMID:Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. 770 86

Systemic administration of the nitric oxide (NO) synthase inhibitor Nomega-nitro--arginine methyl ester (L-NAME) to rabbits bearing a corneal implant blocked vascular endothelial growth factor (VEGF), but not basic fibroblast growth factor (bFGF)-induced angiogenesis. L-NAME completely blocked angiogenesis induced by VEGF-transfected MCF-7 breast carcinoma cells and the cells remained dormant in the cornea. Postcapillary endothelial cell migration and growth induced by VEGF were blocked by both the NO synthase inhibitor Nomega-mono-methyl--arginine and by the guanylate cyclase inhibitor LY 83583. We conclude that NO is a downstream imperative of VEGF-, but not bFGF-induced angiogenesis, and propose that the NO synthase/guanylate cyclase pathway is a potential target for controlling tumor angiogenesis in response to VEGF. Our studies support recent evidence that VEGF and bFGF induce angiogenesis by different mechanistic pathways using the alphavbeta5 and alphavbeta3 integrins, respectively.
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PMID:Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. 1130 96

Thickening of the arterial intima and smooth muscle cell (SMC) proliferation remain major problems after vascular surgery and other types of vascular manipulations. We studied the effect of endothelial cell (EC)-specific vascular endothelial growth factor (VEGF) gene transfer on the thickening of the intima using a silicone collar inserted around carotid arteries that acted both as the agent that caused intimal SMC growth and as a reservoir for the transfected gene. The model preserved EC integrity and permitted direct extravascular gene transfer without any intravascular manipulation. Compared to beta-galactosidase (lacZ)-transfected control arteries, plasmid/liposome-mediated VEGF gene transfer significantly reduced intimal thickening 1 week after the gene transfer. Administration to the experimental animals of the nitric oxide (NO) synthase inhibitor L-NAME abolished the difference in intimal thickening between VEGF and lacZ-transfected arteries. Furthermore, VEGF caused NO release from cultured human umbilical vein EC. It is concluded that extravascular VEGF gene transfer attenuates intimal growth and could be useful for the prevention of intimal thickening during vascular surgery. Our results further suggest that VEGF may reduce SMC proliferation via a mechanism that involves VEGF-induced NO production from the endothelium.
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PMID:VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries. 935 23

Increased microvascular permeability, which occurs in conditions such as the adult respiratory distress syndrome and diabetes mellitus, is related to physicochemical alterations in the microvascular barrier. We postulate that, in part, capillary pericytes affect microvascular permeability via production of a vasoactive cytokine, viz, vascular endothelial growth factor (VEGF), also known as vascular permeability factor. The goal of the present study was to evaluate the effects of phorbol myristate acetate (PMA), a substance known to produce nonhydrostatic pulmonary edema in intact animals, on VEGF gene expression in pericyte cultures. Microvascular pericytes were isolated from bovine retinas using magnetic microspheres coated with 3G5 monoclonal antibody. Pericyte identity was confirmed both morphologically and by immunostaining for alpha-smooth muscle actin and 3G5 ganglioside. The cultured pericytes were stimulated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 x 10(-4) mmol/L), angiotensin II (1 x 10(-6) mmol/L), and PMA (5 x 10(-8) mmol/L), selected because of their ability to upregulate VEGF mRNA expressions in other cell types. Northern blot analysis was performed using [32P]dCTP labeled human VEGF cDNA (Genentech). Lane-loading differences were normalized using mouse GAPDH control cDNA probe. VEGF mRNA expression was upregulated by PMA (10(-9) to 10(-6) mol/L) in a dose-dependent manner, whereas neither L-NAME nor angiotensin II affected VEGF mRNA expression in pericytes. These results support the hypothesis that pericytes increase permeability of the endothelial barrier through increased VEGF production.
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PMID:Vascular endothelial growth factor mRNA in pericytes is upregulated by phorbol myristate acetate. 945 54

Previously, we demonstrated the role of nitric oxide (NO) in transforming epithelial cells from a stationary to locomoting phenotype [E. Noiri, T. Peresleni, N. Srivastava, P. Weber, W.F. Bahou, N. Peunova, and M. S. Goligorsky. Am. J. Physiol. 270 (Cell Physiol. 39): C794-C802, 1996] and its permissive function in endothelin-1-stimulated endothelial cell migration (E. Noiri, Y. Hu, W. F. Bahou; C. Keese, I. Giaever, and M. S. Goligorsky, J. Biol: Chem. 272: 1747-1753, 1997). In the present study, the role of functional NO synthase in executing the vascular endothelial growth factor (VEGF)-guided program of endothelial cell migration and angiogenesis was studied in two independent experimental settings. First, VEGF, shown to stimulate NO release from simian virus 40-immortalized microvascular endothelial cells, induced endothelial cell transwell migration, whereas NG-nitro-L-arginine methyl ester (L-NAME) or antisense oligonucleotides to endothelial NO synthase suppressed this effect of VEGF. Second, in a series of experiments on endothelial cell wound healing, the rate of VEGF-stimulated cell migration was significantly blunted by the inhibition of NO synthesis. To gain insight into the possible mode of NO action, we next addressed the possibility that NO modulates cell matrix adhesion by performing impedance analysis of endothelial cell monolayers subjected to NO. The data showed the presence of spontaneous fluctuations of the resistance in ostensibly stationary endothelial cells. Spontaneous oscillations were induced by NO, which also inhibited cell matrix adhesion. This process we propose to term "podokinesis" to emphasize a scalar from of micromotion that, in the presence of guidance cues, e.g., VEGF, is transformed to a vectorial movement. In conclusion, execution of the program for directional endothelial cell migration requires two coexisting messages: NO-induced podokinesis (scalar motion) and guidance cues, e.g., VEGF, which imparts a vectorial component to the movement. Such a requirement for the dual signaling may explain a mismatch in the demand and supply with newly formed vessels in different pathological states accompanied by the inhibition of NO synthase.
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PMID:Podokinesis in endothelial cell migration: role of nitric oxide. 945 33

1. Hydraulic conductivity (Lp) of the wall of perfused microvessels has previously been shown to be chronically increased 24 h after a 10 min perfusion with vascular endothelial growth factor (VEGF). In order to investigate this further, Lp and the effective oncotic pressure difference (f3DeltaPi) acting across the vessel walls was measured before exposure to VEGF and 24 h later after the mesentery had been replaced in the abdominal cavity. 2. Acute 10 min perfusion with VEGF did not chronically change f3DeltaPi despite chronically increasing Lp 6.8 +/- 1.2-fold. This suggests that pathways formed 24 h after perfusion with VEGF which increase hydraulic conductivity of the capillary walls have the same reflection coefficient as those present before VEGF. 3. Acute 10 min perfusion with VEGF significantly increased the diameter of vessels after 24 h by 48 +/- 13%. To determine whether this was due to changes in the compliance of the vessel wall, the distensibility of microvessels was measured before and 24 h after perfusion with VEGF. The distensibility was increased 45 +/- 15% by VEGF but this was not great enough to account for the increase in diameter. 4. The chronic increase in Lp could be attenuated by inhibition of nitric oxide synthase with L-NAME. In addition, the chronic increase in permeability was correlated with the acute response to VEGF (r = 0.71, P < 0.01) suggesting that the acute and chronic changes may be related. 5. These results show that VEGF chronically increases Lp without affecting the oncotic reflection coefficient. This may be due to reduced pore path length, or increased small pore numbers, which are properties of fenestrated capillaries. They also show that VEGF increases microvascular distensibility and diameter.
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PMID:The chronic effect of vascular endothelial growth factor on individually perfused frog mesenteric microvessels. 978 72

Using the rat mesenteric window angiogenesis assay, we studied the systemic effect of the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester, L-NAME, on angiogenesis induced by basic fibroblast growth factor (bFGF), interleukin-1-alpha (IL-1) or vascular endothelial growth factor (VEGF165). Using technically independent morphometric and image analysis methods, the angiogenic response was quantified in variables related to (i) microvascular spatial extension and (ii) microvascular density. The test tissue, which is natively vascularized and lacks significant angiogenesis physiologically, was unaffected by surgical intervention. Two daily intraperitoneal injections of bFGF (2.20 nmole), IL-1 (1.18 nmole) and VEGF165 (480 pmole) for 5 days elicited significant angiogenesis in the mesenteric windows. L-NAME (0.5 g/L in drinking water) caused further enhancement of the angiogenic response produced by human recombinant bFGF (p<0.001), bovine purified bFGF (p<0.05) or murine recombinant IL-1 (p<0.05). In contrast, the L-NAME treatment did not affect the angiogenic response produced by human and murine recombinant VEGF165. These data suggest that nitric oxide can act as an endogenous suppressor of mammalian de novo angiogenesis, which is a new finding, and, moreover, that angiogenesis induced by VEGF165 on the one hand and by bFGF and IL-1 on the other in the rat mesenteric window depends on different pathways.
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PMID:Nitric oxide suppresses bFGF- and IL-1-alpha-mediated but not VEGF165-mediated angiogenesis in natively vascularized mammalian tissue. 1005 22

VEGF-A induces angiogenesis and regulates endothelial function via production and release of nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS). While the upregulation of eNOS expression has been shown to be mediated via VEGF receptor KDR, there is controversy about which of the VEGF receptors triggers the release of nitric oxide in endothelial cells. In order to determine the levels of NO produced in response to VEGF-A stimulation in different endothelial cells, a reporter assay measuring the formation of cGMP as the direct product of NO-induced activation of guanylate cyclase was performed. Using two independent experimental strategies, we were able to prove that VEGF receptor KDR, but not VEGF receptor Flt-1, can induce NO release in endothelial cells. First, we made use of porcine aortic endothelial cells (PAE) expressing either KDR or Flt-1. While KDR-expressing PAE/KDR cells responded to VEGF-A stimulation with a significant elevation of intracellular cGMP already after 2 min, Flt-1-expressing PAE/Flt-1 cells did not show any signal in this RIA-based cGMP assay. In a second experimental strategy freshly isolated human umbilical vein endothelial cells (HUVEC) were stimulated either with the KDR-specific ligand VEGF-E or with the Flt-1-specific ligand PIGF-2. VEGF-E induces cGMP elevation in this setting, while PIGF-2 was unable to do so, clearly demonstrating that KDR is responsible for NO release in endothelial cells. In our assays cGMP formation is fully dependent on NO generation since the NOS inhibitor L-NAME can block this VEGF-A-induced action. These data show that the VEGF receptor KDR is responsible for NO release in endothelial cells, highlighting a new function of KDR and further supporting the importance of KDR in the regulation of the vasculature.
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PMID:A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. 1060 Apr 73

Reactive oxygen species (ROS) play an important role in signaling pathways stimulated by growth factors in vascular cells. We investigated whether vascular endothelial growth factor (VEGF), which is upregulated in diabetic retinopathy and atherosclerosis, is able to enhance production of ROS, and if so, whether ROS modulate endothelial permeability. ROS levels in bovine retinal microvascular endothelial cells (BMEC) were measured by the oxidation of 2', 7'-dichlorodihydrofluorescein (DCHF), and permeability was examined by monitoring the passage of albumin through BMEC monolayers. VEGF stimulated oxidation of DCHF in BMEC, an effect which was inhibited by superoxide dismutase (SOD) and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), but not by D-NAME. Urate, a scavenger of peroxynitrite, attenuated the VEGF-induced oxidation of DCHF. VEGF elicited a significant increase in the macromolecule permeability of BMEC monolayers within 30 min. SOD did not modify the basal or the VEGF-stimulated hyperpermeability, but the combination of SOD and VEGF induced a transient reduction in permeability after 10 min. L-NAME, but not D-NAME, enhanced VEGF-induced hyperpermeability without affecting basal values. Urate did not modify the VEGF-induced changes in permeability. In conclusion, VEGF stimulates oxidation of DCHF, which most likely represents peroxynitrite formation, and induces an increase in permeability of BMEC monolayers. Activation of NO synthase seems to counteract this stimulatory effect of VEGF on endothelial permeability.
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PMID:Significance of nitric oxide and peroxynitrite in permeability changes of the retinal microvascular endothelial cell monolayer induced by vascular endothelial growth factor. 1062 27

The regulation of vascular wall homeostasis by nitric oxide (NO) generated by endothelium is being intensively studied. In the present paper, the involvement of NO in the vascular endothelial growth factor (VEGF), insulin or leptin-stimulated proliferation of human endothelial cells (HUVEC) was measured by [3H]thymidine or bromodeoxyuridine incorporation. VEGF and insulin, but not leptin, increased NO generation in HUVEC, as detected with ISO-NO electrode. Proliferation of HUVEC induced by leptin was not changed or was higher in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME) a nitric oxide synthase (NOS) inhibitor. In contrast, L-NAME blunted the proproliferative effect of VEGF and insulin. Furthermore, we demonstrated that, in human arterial smooth muscle cells (hASMC) transfected with endothelial NOS (eNOS) gene, the generation of biologically active VEGF protein was NO-dependent. Inhibition of NO generation by L-NAME decreased the synthesis of VEGF protein and attenuated HUVEC proliferation induced by conditioned media from transfected hASMC. Endothelium-derived NO seems to participate in VEGF and insulin, but not leptin, mitogenic activity. Additionally, the small amounts of NO released from endothelial cells, as mimicked by eNOS transfection into hASMC, may activate generation of VEGF in sub-endothelial smooth muscle cells, leading to increased synthesis of VEGF protein necessary for turnover and restitution of endothelial cells.
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PMID:Nitric oxide mediates the mitogenic effects of insulin and vascular endothelial growth factor but not of leptin in endothelial cells. 1069 78


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