Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States

Abstract

Background-Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states. Methods and Results-The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes. Conclusions-The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.

Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling

“…Furthermore, the deep reduction of the insulin effects on the HIF-1/VEGF pathway we observed in VSMC taken from a well-known animal model of insulin resistance supports the hypothesis that this phenomenon can play a role in the already observed reduction of vascularisation in the insulin-resistant states [1,2].…”

“…The reduction of the effects of insulin on the HIF-1/ VEGF pathway in VSMC from an animal model of insulinresistance and obesity could be an aspect of this 'growth factor dysfunction', providing a possible molecular basis for the reduced formation of new vessels in the insulinresistant states [1,2] that probably contributes to the increased prevalence of cardiovascular events observed in obesity [50].…”

“…Also, body mass index independently influences the degree of collateral development in patients with coronary artery disease [1]. Impairment of vascular endothelial growth factor (VEGF) synthesis/action could play a role in this phenomenon, as observed in insulinresistant rats [2].…”

Obesity is associated with impaired coronary collateral vessel development

“…It was shown in an animal study that VEGF mRNA levels were decreased in cardiac tissues of animals with diabetic state, suggesting a blunted response to hypoxia and decreased collateral vessel development. 21 More interestingly, in the same study, it was also shown that VEGF mRNA levels were decreased similarly in insulin resistance without the presence of clinical diabetes, suggesting that other metabolic factors can regulate the expression of VEGF. Insulin resistance, which is a part of the metabolic syndrome, may be responsible for decreased VEGF response due to lack of insulin to induce VEGF expression.…”

Hyperglycemia-Induced Defects in Angiogenesis in the Chicken Chorioallantoic Membrane Model

“…The expression level of VEGF, the major vascular growth factor, has been found to be decreased by hyperglycemia in models where impaired angiogenesis was observed (7,20,21,24,25) and in fibroblasts isolated from diabetic embryos (26). The expression level of VEGF was found to be unaltered by hyperglycemia in other models (27,28) and increased at sites of aberrant angiogenesis in diabetic patients, particularly in the retina of diabetic patients with proliferative diabetic retinopathy (29).…”