Vascular complications of type 2 diabetes: tyrosine phosphorylation of the endothelial nitric oxide synthase (eNOS)

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Up to 80% of deaths in patients with diabetes are due to the associated cardiovascular complications. Endothelial dysfunction is an early event in disease development and is characterised by the decreased production of endothelium-derived nitric oxide (NO). This not only affects vascular tone and homeostasis but also results in the impaired mobilization of progenitor cells from the bone marrow. The activity of the endothelial NO synthase (eNOS) is regulated by Ca2+-dependent and –independent processes; particularly by its posttranslational modification by phosphorylation. We have recently identified a novel regulatory tyrosine residue within eNOS (Tyr657) that attenuates enzyme activity and linked this event with the activation of the redox- and insulin-sensitive tyrosine kinase, Pyk2. This proposal aims to determine the extent to which Pyk2 activation and eNOS Tyr657 phosphorylation underlies the vasculopathy associated with diabetes. Moreover as eNOS determines the restorative capacity of circulating progenitor cells as well as their mobilization from the bone marrow niche, we plan to assess the role of Pyk2 and tyrosine phosphatases in regulating the angiogenic potential of healthy and diabetic progenitor cells as well as the mobilization of these cells from the bone marrow, again under control and diabetic conditions. Studies in animal models will be complemented by studies on human cells isolated from healthy and diabetic patients. The organisation of the project makes optimal use of the expertise available at the two locations and there is a clear synergy expected by the close collaboration of the two groups.