Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.
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PMID:Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. 750 44

Ischemia often precedes neovascularization. In ocular neovascularization, such as occurs in diabetic retinopathy, a diffusible angiogenic factor has been postulated to be produced by ischemic retina and to lead to neovascularization of the retina, optic nerve, or iris. However, no angiogenic factor has been conclusively identified that satisfies this hypothesis. Vascular endothelial growth factor/vascular permeability factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific for endothelial cells, and is upregulated by hypoxia. We investigated the association of VEGF with the development of experimental iris neovascularization in the cynomolgus monkey. Following the production of retinal ischemia by laser occlusion of all branch retinal veins, VEGF was increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascularization. Northern analysis and in situ hybridization revealed that VEGF messenger RNA is upregulated in the ischemic retina. These observations support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.
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PMID:Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. 752 77

Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific angiogenic growth factor. VEGF gene transfer strategies to stimulate focal angiogenesis could be used to ameliorate myocardial ischemia. To induce angiogenesis in vivo, we have constructed a replication-defective herpes simplex virus type 1 (HSV-1) amplicon vector that places the human VEGF-165 cDNA under the transcriptional control of the HSV immediate-early 4/5 promoter (HSVhvegf). Transduction of NIH 3T3 fibroblasts with HSVhvegf resulted in the secretion of high levels of biologically active VEGF, as assayed by microvascular endothelial mitogenesis. By use of an ex vivo protocol, BLK-CL4 fibroblasts were transduced with HSVhvegf or control HSVlac virus (expressing Escherichia coli beta-galactosidase), resuspended in basement membrane extract (matrigel), and coinjected subcutaneously into syngeneic C57BL/6 mice. One week later, the matrigel plugs with HSVhvegf showed a strong angiogenic response, in contrast to the plugs with HSVlac-transduced fibroblasts. These data indicate that transduction with HSVhvegf virus can induce an angiogenic response in vivo and suggest that this is a viable gene therapy approach for tissue ischemia.
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PMID:Expression of vascular endothelial growth factor from a defective herpes simplex virus type 1 amplicon vector induces angiogenesis in mice. 753 Jun 6

Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of vascular endothelial growth factor in cardiac myocytes. 772 92

Vascular endothelial growth factor (VEGF or vascular permeability factor), a direct-acting, endothelial cell-specific mitogen, has been suggested to be involved in development and maintenance of vasculatures in tumor neovascularization and in normal tissues. To investigate possible roles of VEGF in ischemic hearts, we studied induction of VEGF mRNA by ischemia and hypoxia using coronary artery-ligated hearts in vivo and perfused hearts and cultured myocardial cells in vitro. VEGF mRNA was potently induced by ischemia in the heart in vivo. In perfused hearts, maximum expression was rapidly induced (within 30 min) by transient reversible ischemia (5-10 min of ischemia) and lasted at least 3 h. Induction was also caused by hypoxia, which was confirmed in perfused hearts and cultured myocardial cells. These results suggest that induction of VEGF mRNA is upregulated by oxygen deprivation in the heart and that not only infarction but also chronic ischemia in the clinical setting could induce VEGF as a potent angiogenesis factor to stimulate coronary collateral formation.
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PMID:Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. 797 26

Vascular endothelial growth factor (VEGF) is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. By alternative splicing of mRNA, VEGF may exist as one of four different isoforms that have similar biological activities but differ markedly in targeting and bioavailability. The VEGF receptors are specifically expressed in the cell surface of vascular endothelial cells. Recent studies point to VEGF as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. Furthermore, VEGF appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. The VEGF mRNA is up-regulated in the majority of human tumors and the VEGF protein is increased in the aqueous and vitreous humors of patients with proliferative retinopathies. Anti-VEGF antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and also can inhibit angiogenesis in animal models of intraocular neovascularization. Therefore, strategies aimed at antagonizing VEGF may form the basis for an effective treatment of tumors and retinopathies. Furthermore, VEGF-induced angiogenesis is sufficient to achieve a therapeutic endpoint in models of coronary or limb ischemia.
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PMID:The role of vascular endothelial growth factor in pathological angiogenesis. 853 62

Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, has therapeutic benefit in animal models of coronary or limb ischemia. However, the hemodynamic effects of VEGF have not been investigated. We examined the effects of VEGF on hemodynamics and cardiac performance. Mean arterial pressure (MAP), heart rate (HR), cardiac output, stroke volume, left ventricular (LV) dP/dt, and hematocrit were measured before and after intravenous injection of VEGF in conscious, instrumented rats. VEGF caused a dose-dependent reduction in MAP and an associated increase in HR. VEGF (250 micrograms/kg) significantly decreased cardiac output and stroke volume without affecting the inotropic state of the left ventricle, as determined by dP/dt. VEGF significantly increased hematocrit. Furthermore, VEGF did not affect contractility or HR in the isolated rat heart in vitro. The data suggest that the VEGF-induced decrease in cardiac output is due to reduced stroke volume, which may be caused by a decrease in venous return rather than a direct effect on myocardial contractility. In addition, pretreatment with N omega-nitro-L-arginine methyl-ester (L-NAME), a nitric oxide (NO) synthase inhibitor, significantly attenuated the depressor and tachycardic responses to VEGF, suggesting that VEGF-induced hypotension may be mediated by NO.
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PMID:Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. 876 51

Since the pioneer work of Michaelson in 1947 reporting that retinal ischemia induces the release of soluble angiogenic compounds, numerous studies have been conducted to identify the molecular structure of such messengers. In the early 1980s, the deciphering of angiogenic factor-signaling pathways and their description in the retina focused attention on growth factors. Vascular endothelial growth factor, the major candidate identified in 1992, induces in vivo angiogenesis and vascular permeability. Its expression is enhanced in vitro by hypoxia and hypoglycaemia; and its immunoreactivity is increased in diabetic patients. A decrease in its bioavailability reduces the intensity of neovascularization.
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PMID:Vascular endothelial growth factor and retinal neovascularisation: a new therapeutic approach for diabetic retinopathy. 876 74

The carbohydrate moieties of glycoprotein hormones or growth factor molecules may have a variety of effects that impact biological potency. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a 45 kD heparin-binding, endothelial cell (EC) specific mitogen with a putative N-linked glycosylation site. Recent studies have shown that VEGF/VPF may successfully augment collateral development in animal models of myocardial and hindlimb ischemia. The extent to which glycosylation of the 75 asparagine site affects the angiogenic properties of VEGF/VPF has not been studied in vivo. Specifically unaddressed to date is the concern that nonglycosylated VEGF/VPF may be less stable, and therefore characterized by a shorter half-life, reducing its utility for therapeutic angiogenesis. Accordingly, the purpose of this study was to investigate the extent to which posttranslational modification, specifically glycosylation, mofies the angiogenic properties of VEGF/VPF in vivo. Glycosylated (g+) recombinant human VEGF165 was purified from media conditioned by Chinese hamster ovary (CHO) cells. Nonglycosylated (g-) VEGF165 was expressed, purified and refolded from E. coli. The purity of both materials was assessed by silver-stained SDS/PAGE and characterized by the presence of a single amino terminal sequence as indicated by Edman degradation. Tryptic mapping by reverse-phase HPLC confirmed that the potential glycosylation site at 75 asparagine was occupied by N-linked carbohydrate for the Chinese hamster ovary-derived VEGF/VPF, but not for E. coli-derived VEGF/VPF. The mitogenic effects of Chinese hamster ovary-derived (g+) VEGF165 and E. coli-derived (g-) VEGF165 wre studied in vitro using microvascular EC. At concentrations of VEGF/VPF ranging from 10(-4) to 10(2) nM, both produced similar concentration-dependent effects on EC proliferation. For in vivo studies, (g-) (n = 8) and (g+) (n = 8) formulations of VEGF/VPF were administered to New Zealand white rabbits with unilateral hindlimb ischemia. For (g-) versus (g+) VEGF/VPF-treated groups, respectively, calf blood pressure ratio was 0.40 +/- 0.04 versus 0.37 +/- 0.04; angiographic score (of collateral vessels) was 0.37 +/- 0.04 versus 0.35 +/- 0.04; capillary density (capillaries/mm2) at necropsy was 246.9 +/- 21.5 versus 253.9 +/- 18.8; and tissue perfusion (colored microspheres) was 92.8 +/- 5.5 versus 90.30 +/- 13.47 (all p = ns). Moreover, intravascular Doppler-based analyses of resting, maximum, and endothelium-dependent flow was similar for (g-) and (g+) VEGF/VPF. These in vitro and in vivo findings establish that the potential for VEGF/VPF to stimulate therapeutic angiogenesis persists unaltered in the nonglycosylated state.
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PMID:The in vivo bioactivity of vascular endothelial growth factor/vascular permeability factor is independent of N-linked glycosylation. 878 Jan 72

Vascular endothelial growth factor is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. The vascular endothelial growth factor receptors are specifically expressed on the cell surface of vascular endothelial cells. Recent studies point to vascular endothelial growth factor as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. In addition vascular endothelial growth factor appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. Antivascular endothelial growth factor antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and can also inhibit angiogenesis in animal models of intra-ocular neovascularization. Furthermore vascular endothelial growth factor administration promotes collateral vessel growth and results in functional improvement in animal models of coronary or limb ischemia.
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PMID:Vascular endothelial growth factor, a specific regulator of angiogenesis. 883 60


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