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)

The causes of venous ulceration remain unclear. Twentieth-century hypotheses concentrated on the possibility that this problem was caused by failure of oxygen delivery to the skin. However, it has been difficult to substantiate these predictions in practice. Although the presence of tissue hypoxia has been suggested by studies in which transcutaneous oxygen tension has been assessed with transducers heated to unphysiological temperatures, when oxygen measurements are made at room temperature there is little evidence of tissue hypoxia. This has led to the assessment of alternative mechanisms of ulcer development. There has been considerable interest in recent years in the inflammatory processes that surround venous ulceration. A complex sequence of events appears to surround the development of leg ulceration. Increased leukocyte activation has been shown in patients with venous disease as well as increased expression of soluble endothelial adhesion molecules. Histologic studies of the skin in patients with chronic venous disease show a perivascular infiltration of the capillaries of the papillary plexus (the most superficial part of the dermis) with monocytes, macrophages, and connective tissue proteins including fibrin. Fibrosis of the skin and subcutaneous tissues may be initiated by increased gene expression and production of transforming growth factor-beta1. Vascular endothelial growth factor may be involved in the capillary proliferation that has been reported in the skin by a number of authors. Increased expression of several tissue metalloproteinases has been reported both in liposclerotic skin and periulcer skin. The tissue inhibitors of metalloproteinases are also increased and the net result is unclear. Treatment of venous disease using micronized purified flavonoid fraction moderates some of the inflammatory markers, including leukocyte ligand expression and endothelial adhesion molecule shedding. These compounds have also been shown to reduce leukocyte-endothelial adhesion in animal models of ischemia-reperfusion injury. Many inflammatory processes have now been shown to be involved in the development of the skin changes in patients with chronic venous disease. However, the precise sequence of events that leads to leg ulceration is still unclear. Pharmacologic treatments aimed at moderating some of these inflammatory processes are now under investigation as potential ways of treating patients with the more advanced stages of venous disease.
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PMID:Update on chronic-venous-insufficiency-induced inflammatory processes. 1151 May 95

Vascular endothelial growth factor (VEGF) is known to play an important role in angiogenesis. Its place in collateral artery growth (arteriogenesis), however, is still debated. In the present study, we analyzed the expression of VEGF and its receptors (Flk-1 and Flt-1) in a rabbit model of collateral artery growth after femoral artery occlusion. Hypoxia presents the most important stimulus for VEGF expression. We therefore also investigated the expression level of distinct hypoxia-inducible genes (HIF-1alpha, LDH A) and determined metabolic intermediates indicative for ischemia (ATP, creatine phosphate, and their catabolites). We found that arteriogenesis was not associated with an increased expression of VEGF or the mentioned hypoxia-inducible genes. Furthermore, the high-energy phosphates and their catabolites were entirely within normal limits. Despite the absence of an increased expression of VEGF and its receptors, collateral vessels increased their diameter by a factor of 10. The speed of collateral development could be increased by infusion of the chemoattractant monocyte chemotactic protein-1 but not by infusion of a 30 times higher concentration of VEGF. From these data, we conclude that under nonischemic conditions, arteriogenesis is neither associated with nor inducible by increased levels of VEGF and that VEGF is not a natural agent to induce arteriogenesis in vivo.
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PMID:Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. 1167 2

Inflammatory disturbances in the liver microcirculation have been associated with preservation injury of hepatic grafts. Vascular endothelial growth factor (VEGF), a proinflammatory growth factor released by hepatocytes, acts on sinusoidal endothelial cells, but its implication in graft injury is still unclear. We studied VEGF production by rat hepatocytes after cold ischemia and warm reoxygenation and compared the capacity of University of Wisconsin (UW) and sodium-lactobionate-sucrose (SLS) preservation solutions to maintain this hepatocellular function. Isolated hepatocytes were kept for 0, 24, and 48 hours at 4 degrees C in either solution (cold ischemia), then incubated for 1 to 24 hours at 37 degrees C (warm reoxygenation). We assessed cell viability and production of VEGF messenger RNA (mRNA) and protein. Cell viability decreased in a linear time-dependent fashion by 10% after 48 hours of cold preservation and by an additional 40% after 24 hours of warm culture. Very little VEGF mRNA could be detected after up to 48 hours of simple cold preservation in either solution. However, subsequent warm culture led to a robust and rapid increase in VEGF mRNA expression within the first hour, which declined to close to background levels within 8 to 12 hours in culture. This effect was more important in cells preserved in SLS than UW solution. Similarly, cold preservation alone did not trigger VEGF secretion. VEGF secretion was detected after culturing hepatocytes at 37 degrees C and reached a maximal secretion rate within 12 to 15 hours. However, VEGF production by preserved cells was reduced compared with unstored cells. In conclusion, cold ischemia and warm reoxygenation triggers VEGF mRNA expression by hepatocytes, but subsequent VEGF secretion is partially impaired, suggesting posttranslational defects.
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PMID:Vascular endothelial growth factor production by isolated rat hepatocytes after cold ischemia-warm reoxygenation. 1169 36

Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1alpha subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts. In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1alpha accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was found to be activated by mechanical stress and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction of HIF-1alpha and VEGF was suppressed by gadolinium (a stretch-activated channel inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest that HIF-1alpha plays an important role in the induction of VEGF in nonischemic and mechanically stressed myocardium, and that this is regulated by stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this signaling pathway, which induces HIF-1alpha, seems to play an important role in the adaptation of the myocardium to stresses. The full text of this article is available at http://www.circresaha.org.
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PMID:Early expression of myocardial HIF-1alpha in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway. 1183 20

Vascular endothelial growth factor (VEGF) is a potent neovascular inducer. Gene therapeutic delivery of a plasmid DNA encoding VEGF has been shown to impart collateral vessel development in animal models of hindlimb ischemia. Constitutive, long-lived expression of VEGF through gene transfer, however, may result in hypervascularization and/or leaky blood vessels. To that end, the introduction of regulated VEGF gene transfer technology may provide a safer and more controlled therapy for ischemic tissues. We developed a glucocorticoid-regulated plasmid vector (pNGVL-hAP/GRE(5)-vegf-pA) for modulating VEGF gene expression. This plasmid possessed five tandem repeats of the glucocorticoid-responsive element and adenovirus major-late promoter driving the expression of the VEGF(165) cDNA. Intramuscular delivery of this plasmid to mice, and subsequent treatment with the synthetic glucocorticoid dexamethasone (DEX), led to greatly enhanced VEGF expression. Similar delivery to the gracillis muscle of New Zealand white rabbits that had undergone ligation of their femoral artery to induce ischemia exhibited increased VEGF expression and collateral vessel development only in the presence of DEX. Additionally, reintroduction of DEX at a time point during which initial VEGF transgene levels had subsided resulted in a vigorous reinduction of VEGF transgene expression. This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization.
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PMID:Glucocorticoid-regulated VEGF expression in ischemic skeletal muscle. 1186 20

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.
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PMID:Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. 1194 24

Vascular endothelial growth factor (VEGF) gene therapy may be useful for the treatment of lower-limb ischemia. The objectives of this study were to evaluate safety and angiographic and hemodynamic responses of local catheter-mediated VEGF gene therapy in ischemic lower-limb arteries after percutaneous transluminal angioplasty (PTA). For this study, we recruited patients with chronic lower-limb ischemia and atherosclerotic infrainguinal occlusion or stenosis suitable for PTA. In the study, 18 patients received 2x10(10) plaque-forming units (pfu) VEGF-adenovirus (VEGF-Ad), 17 patients received VEGF-plasmid/liposome (VEGF-P/L; 2000 microg of VEGF plasmid, 2000 microl of DOTMA:DOPE), and 19 control patients received Ringer's lactate at the angioplasty site. Digital subtraction angiography (DSA) was used to evaluate vascularity before, immediately after, and 3 months after the PTA. Clinical follow-up data, basic laboratory tests, and ankle-brachial index (ABI) were evaluated. Primary endpoint was DSA analysis of vascularity, and secondary endpoints were restenosis rate, Rutherford class, and ABI after 3 months follow-up. No major gene transfer-related side effects or differences in laboratory tests were detected between the study groups. However, anti-adenovirus antibodies increased in 61% of the patients treated with VEGF-Ad. For the primary endpoint, follow-up DSA revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site (VEGF-Ad P=0.03, VEGFP/L P=0.02) and in the VEGF-Ad group in the region of the clinically most severe ischemia (P=0.01). As for the secondary endpoints, mean Rutherford class and ABI showed statistically significant improvements in the VEGF-Ad and VEGF-P/L groups, but similar improvements were also seen in the control patients. We conclude that catheter-mediated VEGF gene therapy is safe and well tolerated. Angiography demonstrated that VEGF gene transfer increased vascularity after PTA in both VEGF-Ad- and VEGF-P/L-treated groups.
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PMID:Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. 1209 13

Vascular endothelial growth factor(VEGF) is a highly specific mitogen promoting the formation of blood vessels in embryogenesis and wound healing. It is also a potent inducer of vascular permeability. It is a member of the cystine knot growth factor superfamily. A detailed structural and functional characterization of the interactions between VEGF and its receptors is a prerequisite for the design of molecule antagonists. These structural characterizations and biological properties make VEGF an important research object in the fields of neovascularization of ischemia tissues, prognosis of cancers, tumor metastasis, and the gene therapy.
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PMID:Structure and Function of Vascular Endothelial Growth Factor and Its Related Proteins. 1211 85

Vascular endothelial growth factor (VEGF) is an angiogenic peptide that is produced in the brain after ischemia, injury or in malignant gliomas. Since these pathological conditions are associated with the infiltration of microglial cells, we investigated the expression of VEGF receptors (VEGFR) and possible effects of VEGF on cultivated microglial cells. As shown by reverse transcription-polymerase chain reaction and immunocytochemistry, rat microglial cells as well as the murine cell line BV-2 express the VEGFR-1, but not VEGFR-2. Murine VEGF induced 3H-thymidine incorporation into DNA of murine and rat microglial cells as well as chemotaxis in Boyden chamber assays. However, VEGF did not alter the phosphorylation of mitogen-activated protein kinases and only slightly that of the kinase Akt. These results show that microglial cells are targets for VEGF which induces migration and proliferation of these immunocompetent cells in the brain.
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PMID:Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells. 1241 38

Critical limb ischemia is an important clinical problem that often leads to disability and limb loss. Vascular endothelial growth factor (VEGF), delivered either as recombinant protein or as gene therapy, has been shown to promote both collateral artery formation (arteriogenesis) and capillary angiogenesis in animal models of hindlimb ischemia. However, none of the previous studies has demonstrated an improvement in tissue hypoxia, the condition that drives the molecular response to ischemia. Furthermore, the optimal vector and route of gene delivery have not been determined. Recently, adeno-associated viral (AAV) vectors, which efficiently transduce skeletal muscle and produce sustained transgene expression, have been used as gene therapy vectors. We asked whether an intra-arterial injection of AAV-VEGF(165) normalizes muscle oxygen tension by increasing skeletal muscle oxygen tension, and promotes arteriogenesis and angiogenesis in a rat model of severe hindlimb ischemia. We found that AAV-VEGF treatment normalized muscle oxygen tension in the ischemic limb. In contrast, vehicle and AAV-lacZ-treated limbs remained ischemic. Collateral arteries were more numerous in AAV-VEGF-treated rats, but, surprisingly, capillaries were not. We conclude that intra-arterial AAV-mediated gene transfer of AAV-VEGF(165) normalizes muscle oxygen tension and leads to arteriogenesis in rats with severe hindlimb ischemia.
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PMID:Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb. 1257 17


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