UMLS:C0406810 - FACTA Search

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

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

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

We investigated the effects of vascular endothelial growth factor (VEGF(165)) on [Ca(2+)](i)-transient in cultured lymphatic endothelial cells (LEC) and mechanical activity of isolated dog thoracic ducts. VEGF (0.1-10 ng/ml) caused a dose-dependent increase of the [Ca(2+)](i) in LEC. Pretreatment with 10(-5) M genistein or 5x10(-6) M herbimycin A produced a significant reduction of the VEGF-induced [Ca(2+)](i)-transient. In the presence of 10(-6) M thapsigargin, VEGF caused no significant effect on the [Ca(2+)](i)-transient. Pretreatment with Ca(2+)-free solution containing 0.1 mM EGTA produced no significant effect on the peak increase of [Ca(2+)](i) induced by 0.1 or 10 ng/ml VEGF, but significantly depressed the sustained part of [Ca(2+)](i) observed at the higher concentration of VEGF. The VEGF (0.1-10 ng/ml) caused a significant dilation of the isolated lymph vessels with intact endothelium, which were precontracted with U46,619. The 10 ng/ml VEGF-induced dilation was significantly reduced by 3 x 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME). The action of L-NAME was inhibited by the simultaneous application of 10(-3) M L-arginine. Mechanical rubbing of the endothelium also caused significant inhibition of the VEGF-induced dilation. The findings suggest that VEGF(165) may activate the receptor-related tyrosine kinase and cause the release of Ca(2+) from the inositol 1,4, 5-triphosphate-sensitive intracellular Ca(2+) stores in LEC. VEGF(165) also produces endothelium-dependent nitric oxide-mediated dilation of the precontracted isolated lymph vessels.
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PMID:Effects of VEGF on Ca(2+)-transient in cultured lymphatic endothelial cells and mechanical activity of isolated lymph vessels. 1101 85

The angiogenic proteins basic fibroblast growth factor (bFGF; FGF-2) and vascular endothelial growth factor 121 (VEGF(121)) are each able to enhance the collateral-dependent blood flow after bilateral femoral artery ligation in rats. To study the effect of nitric oxide (NO) synthase (NOS) inhibition on bFGF- or VEGF(121)-induced blood flow expansion, the femoral arteries of male Sprague-Dawley rats were ligated bilaterally, and the animals were given tap water [non-N(G)-nitro-L-arginine methyl ester (L-NAME) group; n = 36] or water that contained L-NAME (L-NAME group; 2 mg/ml, n = 36). Animals from each group were further divided into three subgroups: vehicle (n = 12), bFGF (5 microg x kg(-1) x day(-1), n = 12), or VEGF(121) (10 microg x kg(-1) x day(-1), n = 12). Growth factors were delivered via intra-arterial infusion with osmotic pumps over days 1-14. On day 16, after a 2-day delay to permit clearance of bFGF and VEGF from the circulation, maximal collateral blood flow was determined by (85)Sr- and (141)Ce-labeled microspheres during treadmill running. L-NAME (approximately 137 mg x kg(-1) x day(-1)) for 18 days increased systemic blood pressure (approximately 26%, P<0.001). In the absence of L-NAME, collateral-dependent blood flows to the calf muscles were greater in the VEGF(121)- and bFGF-treated subgroups (85 +/- 4.5 and 80 +/- 2.9 ml x min(-1) x 100 g(-1), respectively) than in the vehicle subgroup (49 +/- 3.0 ml x min(-1) x 100 g(-1), P<0.001). In the presence of NOS inhibition by L-NAME, blood flows to the calf muscles were essentially equivalent among the three subgroups (54 +/- 3.0, 56 +/- 5.1, and 47 +/- 2.0 ml x min(-1) x 100 g(-1) in the bFGF-, VEGF(121)-, and vehicle-treated subgroups, respectively) and were not different from the blood flow in the non-L-NAME vehicle subgroup. Our results therefore indicate that normal NO production is essential for the enhanced vascular remodeling induced by exogenous bFGF or VEGF(121) in this rat model of experimental peripheral arterial insufficiency. These results imply that a blunted endothelial NO production could temper vascular remodeling in response to these angiogenic growth factors.
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PMID:VEGF(121)- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production. 1117 52

The role of nitric oxide (NO) in the induction of angiogenesis was evaluated in a murine heart endothelioma cell line (H.end.FB) carrying the mT oncogene. Two clonal derivatives of H.end.FB, H80 and H73, exhibiting different NO synthase (NOS) activities were selected and used in the study. The relationship among NOS activity and tumor cell behaviour (growth, and angiogenic capacity) and the molecular control of gene expression were investigated. H.end.FB and H80 on one side and H73 on the other side exhibited the highest and lowest NOS activity, respectively. Cell growth was inversely correlated to the amount of NO produced by the cell lines. Conversely, in the avascular rabbit cornea assay, H.end.FB and H80 cells were strongly angiogenic, while H73 were poorly angiogenic, indicating that the ability of the cells to induce neovascularization was associated with the extent of NO produced. Consistently, systemic administration to rabbits of the NOS inhibitor N(w)-nitro-L-arginine methyl ester (L-NAME) significantly reduced the angiogenicity of H.end.FB cells. RT-PCR evidenced that H.end.FB expressed mRNA for TGF-beta1 and all VEGF isoforms, VEGF165 being predominantly expressed. NOS inhibition reduced the basal expression of VEGF isoforms, while it markedly potentiated TGF-beta1 expression. These results indicate that the endogenous production of NO in tumor cells can serve as an autocrine/paracrine signalling mechanism of progression, by controlling angiogenic factor/modulator expression.
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PMID:Nitric oxide modulates the angiogenic phenotype of middle-T transformed endothelial cells. 1131 1

Hypoxic preconditioning (8% O2, 3 h) produces tolerance 24 h after hypoxic-ischemic brain injury in neonatal rats. To better understand the ischemic tolerance mechanisms induced by hypoxia, we used oligonucleotide microarrays to examine genomic responses in neonatal rat brain following 3 h of hypoxia (8% O2) and either 0, 6, 18, or 24 h of re-oxygenation. The results showed that hypoxia-inducible factor (HIF)-1- but not HIF-2-mediated gene expression may be involved in brain hypoxia-induced tolerance. Among the genes regulated by hypoxia, 12 genes were confirmed by real time reverse transcriptase-PCR as follows: VEGF, EPO, GLUT-1, adrenomedullin, propyl 4-hydroxylase alpha, MT-1, MKP-1, CELF, 12-lipoxygenase, t-PA, CAR-1, and an expressed sequence tag. Some genes, for example GLUT-1, MT-1, CELF, MKP-1, and t-PA did not show any hypoxic regulation in either astrocytes or neurons, suggesting that other cells are responsible for the up-regulation of these genes in the hypoxic brain. These genes were expressed in normal and hypoxic brain, heart, kidney, liver, and lung, with adrenomedullin, MT-1, and VEGF being prominently induced in brain by hypoxia. These results suggest that a number of endogenous molecular mechanisms may explain how hypoxic preconditioning protects against subsequent ischemia, and may provide novel therapeutic targets for treatment of cerebral ischemia.
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PMID:Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. 1214 88

VEGF is an endothelial cell cytokine that promotes angiogenesis and enhances microvascular permeability. Recently, it has been shown that the protein kinase Akt functions in a key intercellular signaling pathway downstream of VEGF. Here, we employed adenovirus-mediated gene transfer in conjunction with the Miles assay in hairless albino guinea pigs to assess the role of Akt signaling in vascular permeability. VEGF-induced vascular permeability was blocked by the transduction of a dominant negative mutant of Akt. Conversely, transduction of a constitutively active form of Akt promoted vascular permeability in a manner similar to VEGF protein administration. This Akt-mediated increase in vascular permeability was inhibited by the eNOS inhibitor L-NAME. These data show that Akt signaling is both necessary and sufficient for vascular permeability in an in vivo model.
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PMID:Akt signaling mediates VEGF/VPF vascular permeability in vivo. 1245 64

Endothelial nitric oxide synthase (eNOS) phosphorylation increases nitric oxide formation, for example, after VEGF stimulation. We investigated whether nitric oxide formed after overexpression of VEGF or of phosphomimetic eNOS (S1177D) affects PMN-induced myocardial detriment after ischemia and reperfusion. Pigs (n=8 per group) were subjected to percutaneous liposome-based gene transfer by retroinfusion of the anterior interventricular vein 48 h before LAD occlusion (60 min) and reperfusion (24 h). Thereafter, regional myocardial function was assessed as subendocardial segment shortening (SES), and infarct size was determined. Tissue from the infarct region, the noninfarcted area at risk, and a control region was analyzed for NF-kappaB activation (EMSA), tumor necrosis factor (TNF)-alpha, and E-selectin mRNA and infiltration of polymorphonuclear neutrophils (PMN). L-NAME was applied in one group of VEGF-transfected animals. NF-kappaB activition, PMN infiltration in the infarct region, and AAR were reduced after transfection of VEGF or eNOS S1177D, but not after VEGF+L-NAME coapplication. Infarct size decreased, whereas SES improved after either VEGF or eNOS S1177D transfection, an effect inhibited by L-NAME coapplication. Retroinfusion of liposomal VEGF cDNA reduces NF-kappaB-dependent postischemic inflammation and subsequent myocardial reperfusion injury, an effect mediated at least in part by enhanced eNOS phosphorylation.
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PMID:VEGF165 transfection decreases postischemic NF-kappa B-dependent myocardial reperfusion injury in vivo: role of eNOS phosphorylation. 1258 40

Trichloroetheylene (TRI) is an environmental pollutant that has been linked to congenital heart defects (CHD). Endothelial nitric oxide synthase (eNOS) generation of nitric oxide (NO) plays an important role in endothelial cell proliferation, which is considered essential for normal blood vessel growth and development. We hypothesized that TRI alters the balance of NO and superoxide anion (O2-) to impair endothelial cell proliferation. Proliferating endothelial cells were pretreated with TRI (5 microM) and then stimulated with the calcium ionophore, A23187 (5 microM), to determine changes in endothelial cell and eNOS function with respect to NO and O2- generation. Immunoblots of eNOS, phospho-eNOS at serine 1179 (S1179), and the levels of associated heat shock protein 90 (hsp90) were used to define the activation state of eNOS. The effects of TRI (0.05-100 microM) on vascular endothelial growth factor (VEGF, 0.58 nM) induced endothelial cell proliferation were determined from cell counts. TRI decreased A23187-stimulated nitrite + nitrate production from 1.99 +/- 0.90 to 0.89 +/- 0.51 pmol/mg protein (p < 0.05; n = 6). In controls, Lomega-nitroargininemethylester (L-NAME) increased A23187-stimulated O2- production from 0.130 +/- 0.089 to 0.214 +/- 0.071 nmol/min/mg protein (p < 0.05; n = 5). In TRI-treated cultures, however, L-NAME decreased A23187-stimulated O2- production from 0.399 +/- 0.121 to 0.199 +/- 0.055 nmol/min/mg protein (p < 0.05; n = 5). TRI decreased hsp90 associated with eNOS by 46.7% and inhibited VEGF-stimulated endothelial cell proliferation by 12 to 35%. These data show that TRI alters hsp90 interactions with eNOS and induces eNOS to shift from NO to O2- generation. Our findings provide new insight into how TRI alters endothelial and eNOS function to impair VEGF-stimulated endothelial proliferation. Such changes in endothelial function may play an important role in the development of congenital heart defects.
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PMID:Trichloroethylene decreases heat shock protein 90 interactions with endothelial nitric oxide synthase: implications for endothelial cell proliferation. 1265 42

The increase of wall shear stress in capillaries by oral administration of the alpha1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Because endothelial nitric oxide synthase (eNOS) is upregulated in response to elevated wall shear stress, we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) were given to C57BL/6 wild-type mice and eNOS-knockout mice for 14 days. The capillary-to-fiber (C/F) ratio and capillary density (CD; no. of capillaries/mm2) were determined in frozen sections from extensor digitorum longus (EDL) muscles of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles, whereas VEGF (after precipitation with heparin-agarose) and neuronal NOS (nNOS) concentrations were determined in EDL solubilizates. In EDL muscles of C57BL/6 mice treated for 14 days, the C/F ratio was 28% higher after prazosin administration and 11% higher after prazosin and L-NAME feeding, whereas the CD increased by 21 and 13%, respectively. The C/F ratio was highest after day 4 of prazosin treatment and decreased gradually to almost constant values after day 8. Prazosin administration led to elevation of eNOS expression. VEGF levels were lowest at day 4, whereas nNOS values decreased after day 8. In EDL muscles of eNOS-knockout mice, no significant changes in C/F ratio, CD, or VEGF and nNOS expression were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle, albeit other signaling molecules might partially compensate for or contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential downregulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis.
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PMID:Endothelial NOS is main mediator for shear stress-dependent angiogenesis in skeletal muscle after prazosin administration. 1523 96

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