Insulin action on endothelium in angiogenesis
Patients with obesity and type 2 diabetes have increased risk for heart failure and limb amputation, in part because of impaired neovascular response in hypoxic tissue. Insulin action directly on vascular endothelium can activate proangiogenic mechanisms such as generation of nitric oxide (NO). Therefore, insulin resistance in endothelial cells could help explain compromised neovascularization in ischemic tissues in conditions with insulin resistance. Based on strong preliminary data, we hypothesize that insulin action on endothelial cells, through inhibition of the transcription factor FoxO, can regulate angiogenic or angiostatic genes and thereby promote angiogenesis in muscle. In Aim 1, we will determine the contribution to angiogenesis of insulin receptor signaling in endothelial cells. Blood flow, collateral formation, and angiogenesis will be quantitated in the ischemic hindlimb after femoral artery ligation and compared with these parameters in the contralateral leg, using mice with knockout of the insulin receptor restricted to endothelial cells or their littermate controls. In Aim 2, we will determine the relative contribution of FoxO1 or FoxO3 to insulin signaling and cell function in endothelial cell culture by adenovirus-mediated expression of FoxO constructs. We will also screen for insulin-stimulated regulation of 23 genes previously documented as being regulated by FoxO and determine which of these genes mediate proangiogenic cell function by shRNA-mediated knockdown of candidate genes using lentivirus as vectors. Relevance. This work will provide an animal model of impaired angiogenesis in conditions with insulin resistance and identify insulin-regulated genes in endothelial cells which modifies angiogenesis. Ultimately, results from this research may guide development of insulin analogs and insulin sensitizers and identify novel targets for improving heart and limb function in complications of obesity and type 2 diabetes.

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