title: Rosuvastatin enhances angiogenesis via eNOS-dependent mobilization of endothelial progenitor cells.
abstract: 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.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiu-Mei
authors.initials: XM
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Goukassian
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.forename: Yao-Liang
authors.initials: YL
authors.lastname: Tang
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D005464:Fluorobenzenes / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D000068718:Rosuvastatin Calcium; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III