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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1789.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

AMP-Activated Protein Kinase Promotes the Differentiation of Endothelial Progenitor Cells

Xiaoxia Li; Yingying Han; Wei Pang; Chenghong Li; Xuefen Xie; John Y.-J. Shyy; Yi Zhu

From the Department of Physiology and Pathophysiology (X.L., Y.H., W.P., C.L., X.X., Y.Z.) Key Laboratory of Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China; and the Division of Biomedical Sciences (J.Y.-J.S.), University of California, Riverside.

Correspondence to Yi Zhu, MD, Department of Physiology and Pathophysiology, Health Science Center, Peking University, Beijing, 100083, China. E-mail zhuyi{at}hsc.pku.edu.cn

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.

In human cord blood-derived EPCs, VEGF caused the phosphorylation of AMPK and eNOS, increased the expression of EC markers, and increased the angiogenesis of EPCs in vitro and in vivo. Similar effects were observed with lovastatin and AMPK agonist. The activation of AMPK provides a novel mechanism for EPC differentiation.

Key Words: endothelial progenitor cells • differentiation • AMPK • eNOS • angiogenesis