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 is an angiogenic and neurotrophic peptide whose expression is transcriptionally induced in hypoxic tissues through the action of hypoxia-inducible factor-1alpha. To determine if this signaling pathway is activated in the ischemic brain, and might therefore participate in adaptive processes such as angiogenesis and neuroprotection, we examined the expression of vascular endothelial growth factor and hypoxia-inducible factor-1alpha in cerebral cortex and hippocampus following transient global cerebral ischemia in the rat. Northern analysis showed ischemia-inducible expression of multiple vascular endothelial growth factor messenger ribonucleic acid splice variants between 4 and 24h. Western analysis and immunocytochemistry demonstrated the concerted induction of vascular endothelial growth factor and hypoxia-inducible factor-1alpha in the same, apparently neuronal, cells in vulnerable regions of cortex and hippocampus after 15min of ischemia, which persisted for as long as 4 to 72h of reperfusion. These findings demonstrate that hypoxia-sensitive vascular endothelial growth factor signaling can be induced in neurons in global cerebral ischemia in vivo, and are consistent with the hypothesis that ischemic insults trigger hypoxia-sensing and adaptive downstream molecular responses in central neurons.
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PMID:Induction of vascular endothelial growth factor and hypoxia-inducible factor-1alpha by global ischemia in rat brain. 1102 49

Vascular endothelial growth factor is an angiogenic peptide that binds to tyrosine kinase receptors on target cells to activate signal transduction pathways involving phosphatidylinositol 3'-kinase and the serine-threonine protein kinase, Akt. To determine whether this signaling pathway is activated in cerebral ischemia, we examined the expression of vascular endothelial growth factor receptors 1 and 2, and phosphatidylinositol 3'-kinase-activated phospho-Akt, in the cerebral cortex and hippocampus following transient global cerebral ischemia in the rat. Western blot analysis and immunocytochemistry demonstrated induction of vascular endothelial growth factor receptor 1 and 2 expression, and of anti-phosphatidylinositol 3'-kinase-immunoprecipitated phospho-Akt, in vulnerable regions of the cortex and hippocampus after 15 min of global ischemia and 4-72 h of reperfusion. These findings demonstrate that vascular endothelial growth factor receptors and receptor-coupled signal transduction pathways are induced in ischemic brain in vivo, and could therefore participate in endogenous neuroprotective responses to ischemia.
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PMID:Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3'-kinase/Akt signaling by global cerebral ischemia in the rat. 1103 5

Vascular endothelial growth factor (VEGF), a key regulator of vasculogenesis and embryonic angiogenesis, was recently found to be up-regulated in an animal model of stroke. Unlike VEGF, angiopoietin (Ang)-1 and -2, their receptor tie-2, and the associated receptor tie-1 exert their functions at later stages of vascular development, i.e., during vascular remodeling and maturation. To assess the role of the angiopoietin/tie family in ischemia-triggered angiogenesis we analyzed their temporal and spatial expression pattern after middle cerebral artery occlusion (MCAO) using in situ hybridization and immunohistochemistry. Ang-1 mRNA was constitutively expressed in a subset of glial and neuronal cells with no apparent change in expression after MCAO. Ang-2 mRNA was up-regulated 6 hours after MCAO and was mainly observed in endothelial cell (EC) cord tips in the peri-infarct and infarct area. Up-regulation of both Ang-2 and VEGF coincided with EC proliferation. Interestingly, EC proliferation was preceded by a transient period of EC apoptosis, correlating with a change in VEGF/Ang-2 balance. Our observation of specific stages of vascular regression and growth after MCAO are in agreement with recent findings suggesting a dual role of Ang-2 in blood vessel formation, depending on the availability of VEGF.
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PMID:Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. 1107 8

Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, is secreted in ischemic tissue and plays a pivotal role in angiogenesis. We studied whether VEGF administered to a rat muscle flap at the time of ischemia induction would increase microcirculatory flow to the flap. The cremaster muscle flap was isolated on its neurovascular pedicle. Ischemia was induced by clamping the vascular pedicle, and 0.2 ml of either VEGF (0.1 microg) or vehicle (phosphate-buffered saline) was immediately infused into the muscle. After 4 or 6 hours, the clamps were released, and the cremaster was placed in a pocket in the medial thigh for 24 hours. The muscle was then dissected, and microcirculatory measurements were made under intravital microscopy. Six animals were used in each of the four groups. All flaps exposed to 6 hours of ischemia, the duration considered to be critical ischemia, had no significant microcirculatory flow, regardless of treatment with VEGF. In the 4-hour ischemia group, or subcritical ischemia group, red blood cell velocity in arterioles was 14 mm/sec in muscles treated with VEGF and 9 mm/sec in controls (p = 0.02), and capillary flow was 7 per high-power field in muscles treated with VEGF versus 2 per high-power field in controls (p = 0.0005). Thus, VEGF did not alter microcirculatory flow in a muscle flap exposed to critical ischemia, but it did enhance flow to a flap exposed to subcritical ischemia.
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PMID:Improved perfusion after subcritical ischemia in muscle flaps treated with vascular endothelial growth factor. 1112 83

Vascular endothelial growth factor (VEGF) has proven to be one of the most effective growth factors for therapeutic angiogenesis. The biological efficacy of the adeno-associated virus (AAV) vector has recently been demonstrated in muscle tissues, including the heart. Apart from these promising insights into VEGF and the AAV vector, studies on VEGF gene transfer using the AAV vector have been limited. Here, we evaluate AAV-mediated VEGF gene transfer, both in vitro and in vivo, using the AAV-mVEGF vector that contains cDNA for murine VEGF(120) within an HCMV-driven expression cassette. Transient transfection of AAV-mVEGF plasmid significantly increased mVEGF expression in 293T cells. The secreted VEGF in the conditioned medium had strong biological activity, as confirmed by the Miles' vascular permeability assay. Transduction of 293T and HeLa cells with AAV-mVEGF stock of high titer, that is essentially adenovirus-free, showed significantly increased mVEGF expression above that of AAV-eGFP-transduced cells. When human umbilical vein endothelial cells were transduced, a higher level of mVEGF expression, together with higher cell counts, was observed compared to AAV-eGFP-transduced cells. In vivo transduction of mouse tibialis anterior muscle resulted in an increased level of mVEGF expression, and higher capillary-to-myofibre ratio, 8 weeks post-transduction. In a rat hindlimb ischemia model, regional blood flow, as well as the capillary-to-myofibre ratio, was significantly increased at 4 weeks post-transduction. These findings demonstrate the efficient delivery of the VEGF gene using an AAV vector, which has implications for angiogenic gene therapy in ischemic diseases.
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PMID:Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector. 1116 34

Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.
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PMID:Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. 1117 54

Stimulating angiogenesis by gene transfer approaches offers the hope of treating tissue ischemia which is untreatable by currently practiced techniques of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic molecules, making them ideal candidates for novel gene transfer protocols designed to promote new blood vessel growth. In this study, an ex vivo gene therapy approach utilizing cell encapsulation was employed to deliver VEGF and FGF-2 in a continuous and localized manner. C(2)C(12) myoblasts were genetically engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantation in vivo. Therapeutic efficacy was evaluated in a model of acute skin flap ischemia. Capsules were positioned under the distal, ischemic region of the flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing either form of VEGF had no effect on flap survival, but induced a modest increase in distal vascular supply. Delivery of FGF-2 significantly improved flap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization was significantly increased by FGF-2 (P < 0.01), with numerous vessels, many of which had a large lumen diameter, growing in the proximity of the implanted capsules. These results demonstrate that FGF-2, delivered from encapsulated cells, is more efficacious than either VEGF(121) or VEGF(165) in treating acute skin ischemia and improving skin flap survival. Furthermore, these data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia.
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PMID:Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia. 1131 19

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.
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PMID:Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. 1132 59

Diabetic patients are at a 10- to 20-fold increased risk for the development of critical limb ischemia. Vascular endothelial growth factor (VEGF) is critical for the development of collateral blood vessels, which can effectively bypass peripheral arterial occlusions. We therefore set out to determine if the regulation of VEGF in patients with peripheral vascular disease differs in diabetic and nondiabetic patients. Diabetic and nondiabetic patients with peripheral vascular disease were divided into those with or without critical limb ischemia as defined by clinical criteria (rest pain, nonhealing ulcer). Monocytes from peripheral blood were isolated from all patients and the hypoxic induction of VEGF was determined in vitro. In patients without diabetes, we found that there was no significant difference in the hypoxic induction of VEGF between patients with or without critical limb ischemia. However, in diabetic patients we found that patients with critical limb ischemia produced significantly more VEGF than patients without critical limb ischemia (6.3 +/- 1.3 vs. 2.1 +/- 0.3, p < 0.015). We conclude that diabetic patients with critical limb ischemia do not have an impairment in the ability to produce VEGF with hypoxia. Contrary to current dogma, treatment paradigms directed at increasing VEGF production in the diabetic patient with critical limb ischemia might not be beneficial.
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PMID:Regulation of VEGF in diabetic patients with critical limb ischemia. 1141 92

Expressional patterns of the endothelial and neuronal forms of nitric oxide synthase (NOS) in cerebral ischemia were studied utilizing a permanent middle cerebral artery occlusion (PMCAO) model. Motor performance and infarct volumes were determined in the rats. Immunohistochemical staining for eNOS, nNOS and neurofilament were performed at 1, 2, 3, 5, 7 and 14 days after PMCAO. Vascular endothelial growth factor (VEGF) expression was determined by in-situ hybridization. PMCAO caused a reproducible cortical infarct with motor deficits in the rats. Double immunohistochemical stainings indicated that eNOS and nNOS were induced in ischemic neurons. Most stained neurons were positive for both NOS forms but some reacted with only one NOS antibody. nNOS expression peaked at 24-48 h after PMCAO, stained mainly the cytoplasm of core neurons, and disappeared after the 3rd day. eNOS expression increased until the 7th day, stained mainly the cytoplasm and membrane of penumbral cells and disappeared by the 14th day after PMCAO. VEGF expression was significantly induced in the penumbral zone in a similar distribution to eNOS. The anatomical and temporal pattern of VEGF and eNOS induction in the brain after permanent ischemia suggest that these mediators may play a role in protecting penumbral tissue from additional ischemic damage.
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PMID:Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor. 1147 16


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