Molecular mechanisms and modulation of Endothelial Progenitor Cell function in South Asian men

South Asian ethnicity has long been considered a contributory factor in the development of atherosclerosis and cardiovascular disease. Endothelial dysfunction is considered to be the precursor of atherosclerosis, and South Asian ethnicity has been linked to endothelial progenitor cell dysfunction and impaired endothelium dependent vasodilatation. Endothelial progenitor cell (EPC) dysfunction may contribute to ineffective endogenous endothelial repair, although the exact mechanisms remain unclear. This project aimed to validate existing data, and identify signalling pathways and molecular mechanisms that may be involved in EPC dysfunction in healthy South Asian men when compared to matched white European controls. In addition, the study was designed to assess the impact of South Asian ethnicity on EPC function in vivo, and whether modifying the signalling pathways linked with EPC dysfunction improved EPC function. Early outgrowth EPC numbers were significantly lower in South Asian men. EPC numbers were significantly increased in both South Asian and white European groups by treating EPCs with Simvastatin in vitro. Functional parameters such as migration to VEGF, adhesion to fibronectin and endothelial tubule formation induced by EPC conditioned medium were also impaired in South Asian EPCs. Some aspects of functional impairment were improved by Simvastatin. Late outgrowth EPCs derived from South Asian men demonstrated reduced proliferation and increased senescence. Western blot analysis showed reduced basal Akt and endothelial Nitric Oxide Synthase (eNOS) expression in South Asian late EPCs. Vascular repair of injured conduit vessel following transfusion of South Asian late EPCs was significantly impaired - this was rescued by increasing Akt activity using Lentiviral delivery of constitutively active Akt. Abnormal phosphotidyl-inositol-3-kinase/Akt signalling may therefore contribute to EPC dysfunction in South Asian men. These data provide novel insights into mechanisms underlying EPC dysfunction which may contribute to increased atherosclerosis burden in people of South Asian origin. Future research avenues have been identified, which may guide development of novel strategies in preventing and treating cardiovascular disease.