Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although vascular endothelial growth factor-165 (VEGF(165)) regulates numerous angiogenic cellular activities, its complex effects on vascular morphology are not highly quantified. By fractal-based, multiparametric branching analysis of 2D vascular pattern in the quail chorioallantoic membrane (CAM), we report that vessel density increased maximally at lower VEGF concentrations, but that vessel diameter and activity of endothelial nitric oxide synthase (eNOS) increased maximally at higher VEGF concentrations. Following exogenous application of human VEGF(165) to the CAM at embryonic day 7, vessel density and diameter were measured after 24 h at arterial end points by the fractal dimension (D(f)) and generational branching parameters for vessel area density (A(v)), vessel length density (L(v)) and vessel diameter (D(v)) using the computer code VESGEN. The VEGF-dependent phenotypic switch from normal vessels displaying increased vessel density to abnormal, dilated vessels typical of tumor vasculature and other pathologies resulted from an approximate threefold increase in VEGF concentration (1.25 to 5 microg/CAM) and correlated positively with increased eNOS activity. Relative to control specimens, eNOS activity increased maximally to 60% following VEGF treatment at 5 microg/CAM, compared to 10% at 1.25 microg/CAM, and was accompanied by no significant change in activity of inducible NOS. In summary, VEGF(165) induced a phenotypic switch from increased vessel density associated with low VEGF concentration, to increased vessel diameter and increased eNOS activity at high VEGF concentration.
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PMID:A VEGF165-induced phenotypic switch from increased vessel density to increased vessel diameter and increased endothelial NOS activity. 1687 39

This study tested the hypothesis that specific hypoxic molecules, including hypoxia-inducible factor-1alpha (HIF-1alpha), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF), are upregulated within the cerebral cortex of acutely anemic rats. Isoflurane-anesthetized rats underwent acute hemodilution by exchanging 50% of their blood volume with pentastarch. Following hemodilution, mean arterial pressure and arterial Pa(O(2)) values did not differ between control and anemic rats while the hemoglobin concentration decreased to 57 +/- 2 g/l. In anemic rats, cerebral cortical HIF-1alpha protein levels were increased, relative to controls (1.7 +/- 0.5-fold, P < 0.05). This increase was associated with an increase in mRNA levels for VEGF, erythropoietin, CXCR4, iNOS, and nNOS (P < 0.05 for all), but not endothelial NOS. Cerebral cortical nNOS and VEGF protein levels were increased in anemic rats, relative to controls (2.0 +/- 0.2- and 1.5 +/- 0.4-fold, respectively, P < 0.05 for both). Immunohistochemistry demonstrated increased HIF-1alpha and VEGF staining in perivascular regions of the anemic cerebral cortex and an increase in the number of nNOS-positive cerebral cortical cells (3.2 +/- 1.0-fold, P < 0.001). The nNOS-positive cells costained with the neuronal marker, Neu-N, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). These nNOS-positive neurons frequently sent axonal projections toward cerebral blood vessels. Conversely, VEGF immunostaining colocalized with both neuronal (NeuN) and astrocytic markers (GFAP). In conclusion, acute normotensive, normoxemic hemodilution increased the levels of HIF-1alpha protein and mRNA for HIF-1-responsive molecules. nNOS and VEGF protein levels were also increased within the cerebral cortex of anemic rats at clinically relevant hemoglobin concentrations.
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PMID:Increased expression of HIF-1alpha, nNOS, and VEGF in the cerebral cortex of anemic rats. 1697 34

Hypoxia and the Net ternary complex factor (TCF) regulate similar processes (angiogenesis, wound healing, and cellular migration) and genes (PAI-1, c-fos, erg-1, NOS-2, HO-1, and vascular endothelial growth factor genes), suggesting that they are involved in related pathways. We show here that hypoxia regulates Net differently from the other TCFs and that Net plays a role in the hypoxic response in vivo in mice and in cells. Hypoxia induces Net depletion from target promoters, nuclear export, ubiquitylation, and proteasomal degradation. Key mediators of the hypoxic response, the prolyl-4-hydroxylases containing domain proteins (PHDs), regulate Net. PHD downregulation in normoxia leads to Net degradation, and PHD overexpression delays Net downregulation by hypoxia. Net inhibition by RNA interference or mutation leads to altered regulation by hypoxia of the Net targets PAI-1, c-fos, and egr-1. We propose that hypoxia stimulates transcription of target promoters through removal of the repressor function of Net. Interestingly, the hematocrit response to a chemical inducer of hypoxia-like responses (cobalt chloride) is strongly altered in Net mutant mice. Our results show that the Net TCF is part of the biological response to hypoxia, adding a new component to an important pathological and physiological process.
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PMID:The ternary complex factor net is downregulated by hypoxia and regulates hypoxia-responsive genes. 1740 94

In mineralized tissue the process of angiogenesis is required for normal osteogenesis during bone repair and in reconstructive and substitutive surgery, for proper biomaterial/tissue integration. Nanotechnologies have been proposed to improve the compatibility of biomaterials for use in orthopaedic and reconstructive surgery (e.g., nanocrystals). The aim of this study was to determine the effect of nanostructured hydroxyapatite (HA) on angiogenesis. Microvascular endothelial cell survival, proliferation and migration, crucial events in the angiogenic process, were evaluated together with cytoskeleton and biochemical signalling markers. Induction of migration, metalloproteinase (MMP-2) and focal adhesion Kinase (FAK) activity documented the ability of HA nanocrystals to stimulate capillary endothelium toward an angiogenic phenotype. HA concentrations, ranging from 2 to 10 microg/ml, promoted endothelium survival and proliferation, preserved alphavbeta3-integrin localization, stimulated beta-actin reorganization and Akt phosphorylation (98% vs control). Immunoassays for key signalling pathways in angiogenesis (i.e., endothelial nitric oxide synthase (eNOS) and fibroblast growth factor-2 (FGF-2)) demonstrated that HA increased their expression. Moreover, quantitative RT-PCR and Western blotting analysis confirmed that HA nanocrystals exposure up-regulated FGF-2 mRNA by 6 fold and increased 18 kDa protein isoform by 40%. HA enhanced cell responsiveness to vascular endothelial growth factor (VEGF) in terms of NOS activity (1.5 fold over control), increasing the ability of microvascular endothelium to differentiate into capillary-like structures when grown in 3D fibrin gel. In conclusion our data document the proangiogenic properties of HA nanocrystals. This material stimulates endothelial cell functions and biochemical pathways to an extent similar to VEGF, and primes them to VEGF stimulation, leading to differentiation in pseudocapillary formations in 3D matrices.
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PMID:Nanostructured HA crystals up-regulate FGF-2 expression and activity in microvascular endothelium promoting angiogenesis. 1768 92

The production of growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by human bone marrow mesenchymal stem cells (MSCs) may play an important role in their paracrine effects on proliferation, differentiation, and protection. NO is produced during ischemia and may affect MSC function. However, it is unknown whether NO alters the production of VEGF and HGF from MSCs. To study this, human MSCs were stimulated to produce growth factors with TNF or LPS with and without various doses of NO donors or NOS inhibitors. We found that FK409, an NO donor, significantly suppressed the production of VEGF and HGF from human MSCs. Vascular endothelial growth factor in the supernatants of cells treated by 20 nM FK409 (497 +/- 19 pg/mL) was significantly lower compared with controls (625 +/- 34 pg/mL). Similarly, NO donor significantly suppressed the amount of HGF from controls (118 +/- 3 to 40 +/- 2 pg/mL) after treatment with 20 nM FK409. NO donor also abolished the augmentation of VEGF production induced by LPS. The amount of VEGF in the supernatant was 571 +/- 11 pg/mL when cells were treated with 20 nM FK409 and LPS (200 ng/mL), which was significantly lower than groups treated with LPS alone (941 +/- 30 pg/mL). This study constitutes an initial report regarding the effect of NO on human MSC growth factor production.
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PMID:Nitric oxide suppresses the secretion of vascular endothelial growth factor and hepatocyte growth factor from human mesenchymal stem cells. 1839 52

Nitric oxide (NO) plays an important role in maintaining vascular homeostasis. The importance of NO in the vasculature is demonstrated by several experimental conditions, such as vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, the NO metabolic pathway in endothelial cells could be one of the main contributing factors for angiogenesis. Although several methods have been used for measuring in vitro angiogenesis, a proper technique has not been developed for identifying in vivo NO-dependent angiogenesis. This chapter provides a new intravital microscopic method for detecting and measuring NO-dependent angiogenesis in a mouse model. This technique showed strong abdominal neovascularization in wild-type mice, but not eNOS knockout mice, locally injected with VEGF, as well as stimulation of angiogenesis in NO donor-injected mice. This technique also revealed the inhibitory effect of the NOS inhibitor N(G)-iminoethyl-L-ornithine in VEGF-mediated in vivo angiogenesis. This chapter describes intravital microscopy as a new imaging technique for detecting NO-dependent angiogenesis in an animal model.
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PMID:Microscopic technique for the detection of nitric oxide-dependent angiogenesis in an animal model. 1855 47

An endemic peripheral vascular disorder due to chronic arsenic poisoning, named Blackfoot disease (BFD), occurs in Taiwan. BFD causes destruction of vascular endothelial cells, and an anti-endothelial cell IgG antibody was found in the sera of BFD patients. We studied the role of this IgG antibody (BFD-IgG) in modulating proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) and found that a low concentration of BFD-IgG (200 microg/mL) stimulated endothelial cell growth and increased expressions of vascular cell adhesion molecule-1 (VCAM-1), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF). The apoptosis events appeared not altered by addition of BFD-IgG. An in vitro neoangiogenesis assay demonstrated that BFD-IgG promoted the formation of tube-like structures, which was completely abrogated by anti-VEGF neutralizing antibody and partially by NOS inhibitor, L-NAME. We conclude that BFD-IgG at 200 microg/mL results in cell proliferation and enhanced VEGF-dependent angiogenesis in vitro. Those results suggested that a low concentration of BFD-IgG plays a protective role in the pathogenesis or the progression of BFD.
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PMID:Anti-endothelial cell IgG from patients with chronic arsenic poisoning induces endothelial proliferation and VEGF-dependent angiogenesis. 1867 88

Inflammation is an important event in the development of vascular diseases such as hypertension, atherosclerosis, and restenosis. In addition, the stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of critical proinflammatory cytokines that activate potent immune responses. In this study, LPS was found to induce TLR4 expression and increased nitric oxide (NO) production by increasing the expression of inducible nitric oxide synthase (iNOS). Furthermore, LPS was found to induce interleukin (IL)-8 and vascular endothelial growth factor (VEGF) production, as well as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Taken together, these results indicate that LPS induces inflammatory responses in HASMC. Moreover, NOS inhibitor (L-NAME) and anti-TLR 4mAb reduced the LPS-induced NO, IL-8 and VEGF production and ICAM-1 expression. Additionally, TLR4 expression was reduced by NOS inhibitor. Taken together, these results indicate that LPS-induced inflammatory responses are regulated by TLR4 expression and NO production.
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PMID:LPS induces inflammatory responses in human aortic vascular smooth muscle cells via Toll-like receptor 4 expression and nitric oxide production. 1867 2

Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.
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PMID:Collateral circulation: past and present. 1910 49

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAg(h)) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAg(h) mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1alpha, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAg(h) mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1alpha, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAg(h) mice developed cerebral angiogenesis through the HIF-1alpha/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAg(h), the decrease in HIF-1alpha, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.
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PMID:Cerebral adaptations to chronic anemia in a model of erythropoietin-deficient mice exposed to hypoxia. 1910 75


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