In patients with diabetes mellitus, coronary collateral growth and myocardial angiogenesis are significantly impaired, and these may contribute to high mortality in diabetic myocardial infarction. Diabetic impaired angiogenesis is strongly associated with hyperglycemia-induced endothelial cell apoptosis and angiogenic factors signal transduction dysfunction such as VEGF and eNOS/NO signaling. Tie-2 is an endothelial- specific receptor tyrosine kinase. Angiopoietin-1 (Ang-1, agonist) and angiopoietin-2 (Ang-2, antagonist) are the two key ligands of Tie-2 receptor. Ang-1 has been shown to play a critical role in regulating endothelial cell survival and pericytes recruitment, whereas Ang-2 has been identified as a vessel-destabilizing agent that plays a predominant role in controlling angiogenesis or vessel regression. Recent studies reveal that Ang-2 is abnormally raised both in animal models and in diabetic patients. Further, hyperglycemia-induced Ang-2 contributes to pericytes loss in diabetic retinal vasculature. So far, little is known about the functional consequences of hyperglycemia-induced Ang-2 on diabetic myocardial endothelium. Our preliminary data reveals that exposure to high glucose increases Ang-2 expression and blocks Ang-1-induced myocardial endothelial cell migration indicating that an abnormality of Ang-2 has a detrimental effect on diabetic myocardial angiogenesis. Previously, we made a novel observation that Ang-1 stimulates angiogenesis via upregulation of heat shock protein 90 (Hsp90)/eNOS interaction in porcine coronary artery endothelial cells. Therefore, we propose that hyperglycemia-induced Ang-2 disrupts Ang-1/Hsp90 client protein interactions and contributes to myocardial endothelium destabilization and impairment of myocardial angiogenesis. To explore our notion, using db/db diabetic mice model, we will examine whether: (1) Hyperglycemia-induced Ang-2 disrupts Ang-1 mediated Hsp90/client protein interactions, leads to myocardial endothelium apoptosis and destabilization, loss of pericytes and impairment of angiogenesis; and (2) Pretreatment with Ang-1 prevents hyperglycemia-induced myocardial endothelial apoptosis and destabilization via promoting Hsp90/client protein interactions and recruitment of pericytes. Our proposed studies will elucidate important and novel mechanisms underlying hyperglycemia-induced impairment of angiogenesis and should provide a framework for developing new therapeutic strategies for the treatment of diabetic abnormal angiogenesis. ? ? ?
