Endothelial progenitor cell dysfunction: mechanisms and therapeutic approaches.

Endothelial progenitor cells (EPC) are bone-marrow derived circulating cells participating in angiogenesis and vascular homeostasis. Reduced numbers of circulating EPC are observed in patients with various cardiovascular diseases and are related to an increased risk for future cardiovascular events and death. Little is known about functional changes. The aim of this thesis was to study the function of EPC from patients with coronary artery disease (CAD) or with cardiovascular risk factors such as diabetes or advanced age. In particular, underlying molecular mechanisms were examined and potential therapeutic approaches were explored. CAD patients had reduced EPC numbers, which were correlated with increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor. In vitro, ADMA impaired EPC function which could be restored by statin treatment. In addition, EPC number and function decreased with age. Treatment of volunteers with growth hormone increased EPC levels and improved EPC function. Animal and in vitro studies showed the EPC increase to be directly mediated by the insulin-like growth factor 1 (IGF-1), which enhanced endothelial NOS expression of the EPC in a phosphoinositide-3-kinase/Akt dependent manner. Growth hormone-mediated increase in IGF-1 reversed age-related EPC dysfunction. Finally, function of EPC from patients with type II diabetes mellitus was analysed. Uncoupling of eNOS occurred within diabetic EPC and resulted in enhanced superoxide anion formation with subsequent EPC dysfunction. EPC dysfunction was protein kinase C-dependent, associated with reduced intracellular tetrahydrobiopterin (BH4) concentrations and reversible after exogenous BH4 treatment. Impairment of EPC function is likely to contribute to the pathogenesis of vascular disease in diabetes mellitus. In conclusion, mechanisms underlying EPC dysfunction in various cardiovascular diseases were investigated and novel treatment approaches for dysfunctional EPC were explored. The knowledge may provide clues for the therapy and prevention of certain cardiovascular diseases.