Objective—Endothelial progenitor cells (EPCs) can differentiate into endothelial cells (ECs) and participate in postnatal vasculogenesis, but the mechanism of EPC differentiation remains largely unknown. We investigated the role of AMP-activated protein kinase (AMPK) in EPC differentiation and functions.

Methods and Results—Vascular endothelial growth factor caused the phosphorylation of AMPK, acetyl-coenzymeA (CoA) carboxylase (ACC), and eNOS in human cord blood-derived EPCs. The expression of EC markers, including VE-cadherin and intercellular adhesion molecule1 (ICAM-1), was also increased but blocked by Compound C, an AMPK inhibitor. AICAR, an AMPK agonist, increased the phosphorylation of ACC and eNOS and the expression of EC markers in a time- and dose-dependent manner, which reinforces the positive effect of AMPK on EPC differentiation. The effects of AICAR could be blocked by treatment with L-NAME, an eNOS inhibitor. Functionally, AICAR increased but Compound C decreased the angiogenesis of EPCs in vitro and in vivo. Furthermore, lovastatin promoted the activation of AMPK and eNOS, the expression of EC markers, tube formation, adhesion, and in vivo vasculogenesis of EPCs, which could be blocked by treatment with Compound C.

Conclusion—The activation of eNOS by AMPK during EPC differentiation provides a novel mechanism for the pleiotropic effects of statins in benefiting the cardiovascular system.