HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells

Abstract

The finding that circulating endothelial progenitor cells (EPCs) may home to sites of neovascularization and differentiate into mature endothelial cells (ECs) in situ is consistent with "vasculogenesis" (1), a critical paradigm for establishment of the primordial vascular network in the embryo.Our findings (2-7), together with the recent reports from other investigators (8-14), suggest that growth and development of new blood vessels in the adult is not restricted to angiogenesis but encompasses both vasculogenesis and angiogenesis.Although several studies have established angiogenic properties of EPCs (3-5, 15), including physiological mobilization (4) in response to the angiogenic growth VEGF (5), the involved signaling pathways have remained enigmatic.Recently, Akt protein kinase has been shown to act downstream of the angiogenic growth factors VEGF and angiopoietin (16-18) to confer EC survival (18), migration (19), and production of endothelial cell NO (20,21) in response to VEGF.These suggest a potentially important role for Akt signaling in mediating the response of ECs to angiogenic stimuli.Indeed Kureishi et al. have recently shown that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, rapidly activates Akt signaling in ECs, and that this stimulates EC bioactivity in vitro and enhances angiogenesis in vivo ( 22).Statins inhibit the activity of HMG-CoA reductase, which catalyzes the synthesis of mevalonate, a rate-limiting step in cholesterol biosynthesis.The clinical application of statins has already led to important improvements in primary and secondary prevention of coronary artery disease (CAD) in subjects with and without elevated cholesterol levels.Preclinical studies suggest that statins may promote angiogenesis in ischemic limbs ( 22) and protect against ischemia-reperfusion injury of the heart (23), through mechanisms that may be mediated by activation of Akt signaling and endothelium-derived nitric oxide (NO) production in normocholesterolemic animals.Accordingly, we investigated the hypothesis that Akt may constitute a key signaling pathway in the angio-