Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart

Abstract

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.

Plasma Angiopoietin-1, Angiopoietin-2, Angiopoietin Receptor Tie-2, and Vascular Endothelial Growth Factor Levels in Acute Coronary Syndromes

“…VEGF, its receptors, and the Ang/Tie-2 systems are the predominant coordinators for angiogenesis. In vitro experimental studies have shown that VEGF, Ang-2, and Tie-2 but not Ang-1 expression is upregulated in ischemic myocardium, 3,5 whereas clinical studies in patients with ACS (AMI patients) have shown increased peripheral blood VEGF. [7][8][9][10][11] The present study shows that in addition to raised VEGF and Tie-2 levels, Ang-2 levels were also raised in ACS patients within 24 hours of presentation, although Ang-1 levels were not different compared with those of healthy control subjects and SA patients.…”

“…2 VEGF mRNA, protein, and its receptors' expression can be rapidly upregulated in the myocardium within minutes of ischemia (or hypoxia). 3 Indeed, VEGF levels are substantially increased in vivo in ischemic human and animal myocardium. 4,5 Furthermore, increased VEGF can be detected in the peripheral blood of patients with acute myocardial infarction (MI) 6 -10 or refractory angina.…”

Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets

“…29 VEGF, another endothelium-specific growth factor, has been reported to be up-regulated by hypoxia in vitro and by ischemia in vivo. [30][31][32] Therefore, VEGF is a likely mediator in the natural process of ischemia-induced myocardial neovascularization. In the clinical setting, the VEGF induced as a potent angiogenesis factor may not be sufficient to stimulate coronary collateral formation, therefore, administration of recombinant VEGF or VEGF genes to promote angiogenesis will be useful as a treatment for arteriosclerosis obliterans (ASO) and myocardial infarction in animal models and clinical patients.…”

“…Diluted primary antibodies (1A4 1:50, PC-10 1:500, anti-ets-1 1:20) Figure 8 Gel-mobility shift assay for ets binding site in the infarcted hearts. MI, nuclear extracts (20 g) from the myocardium transfected with control vector at 14 days after ligation and transfection with 32 …”

Identification of a Human VPF/VEGF 3′ Untranslated Region Mediating Hypoxia-induced mRNA Stability

“…VPF/VEGF expression has been closely associated with the pathological angiogenesis observed in malignant tumors (Plate et al, 1992; Brown et al, 1993a,b;Weindel et al, 1994; Brown et al, 1995a,b), diabetic retinopathy (Adamis et al, 1994;Aiello et al, 1994), retinopathy of prematurity Pierce et al, 1995;Stone et al, 1995), rheumatoid arthritis (Fava et al, 1994), and coronary artery disease (Sabri et al, 1991;Ladoux and Frelin, 1993;Hashimoto et al, 1994). Tissue hypoxia is a common feature in many of these diseases and VPF/VEGF expression is dramatically up-regulated in human solid tumors adjacent to sites of focal necrosis (Plate et al, 1992;Shweiki et al, 1992; Brown et al, 1993).…”