Rosuvastatin enhances angiogenesis via eNOS-dependent mobilization of endothelial progenitor cells

• Published in: PloS one Vol. 8; no. 5; p. e63126
• Main Authors: Zhou, Junlan, Cheng, Min, Liao, Yu-Hua, Hu, Yu, Wu, Min, Wang, Qing, Qin, Bo, Wang, Hong, Zhu, Yan, Gao, Xiu-Mei, Goukassian, David, Zhao, Ting C, Tang, Yao-Liang, Kishore, Raj, Qin, Gangjian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2013; Public Library of Science (PLoS)
• Subjects: AKT protein; Analysis; Angiogenesis; Animals; Biology; Blood flow; Bone marrow; Bone Marrow - pathology; Cell Differentiation - drug effects; Cell Lineage - drug effects; Cell Movement - drug effects; Cells (biology); Chinese medicine; Differentiation; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelium; Fluorobenzenes - pharmacology; Health aspects; Hindlimb - blood supply; Hindlimb - pathology; Hindlimb - physiopathology; Ischemia; Ischemia - pathology; Ischemia - physiopathology; Kinases; Laboratories; Male; Medicine; Mice; Mice, Inbred C57BL; Neovascularization; Neovascularization, Physiologic - drug effects; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Osteoprogenitor cells; Pyrimidines - pharmacology; Regional Blood Flow - drug effects; Rodents; Rosuvastatin; Rosuvastatin Calcium; Statins; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - enzymology; Sulfonamides - pharmacology; Transplantation; Vascularization; United States > US; Illinois; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063126

Circulating endothelial progenitor cells (circEPCs) of bone marrow (BM) origin contribute to postnatal neovascularization and represent a potential therapeutic target for ischemic disease. Statins are beneficial for ischemia disease and have been implicated to increase neovascularization via mechanisms independent of lipid lowering. However, the effect of Statins on EPC function is not completely understood. Here we sought to investigate the effects of Rosuvastatin (Ros) on EPC mobilization and EPC-mediated neovascularization during ischemic injury. In a mouse model of surgically-induced hindlimb ischemia (HLI), treatment of mice with low dose (0.1 mg/kg) but not high dose (5 mg/kg) significantly increased capillary density and accelerated blood flow recovery, as compared to saline-treated group. When HLI was induced in mice that had received Tie2/LacZ BM transplantation, Ros treatment led a significantly larger amount of endothelial cells (ECs) of BM origin incorporated at ischemic sites than saline. After treatment of mice with a single low dose of Ros, circEPCs significantly increased from 2 h, peaked at 4 h, declined until 8 h. In a growth-factor reduced Matrigel plug-in assay, Ros treatment for 5 d induced endothelial lineage differentiation in vivo. Interestingly, the enhanced circEPCs and post-HLI neovascularization stimulated by Ros were blunted in mice deficient in endothelial nitric oxide synthase (eNOS), and Ros increased p-Akt/p-eNOS levels in EPCs in vitro, indicating these effects of Ros are dependent on eNOS activity. We conclude that Ros increases circEPCs and promotes their de novo differentiation through eNOS pathway.