Essential role of extracellular SOD in reparative neovascularization induced by hindlimb ischemia.
Neovascularization is an important physiological repair mechanism in response to ischemic injury, and its process is dependent on reactive oxygen species (ROS). Overproduction of superoxide anion (O2-) rather contributes to various cardiovascular diseases. The extracellular superoxide dismutase (ecSOD) is one of the major antioxidant enzymes against O2- in blood vessels; however, its role in neovascularization induced by tissue ischemia is unknown. Here we show that hindlimb ischemia of mice stimulates a significant increase in ecSOD activity in ischemic tissues where ecSOD protein is highly expressed at arterioles. In mice lacking ecSOD, ischemia-induced increase in blood flow recovery, collateral vessel formation, and capillary density are significantly inhibited. Impaired neovascularization in ecSOD(-/-) mice is associated with enhanced O2- production, TUNEL-positive apoptotic cells and decreased levels of NO2-/NO3- and cGMP in ischemic tissues as compared with wild-type mice, and it is rescued by infusion of the SOD mimetic tempol. Recruitment of inflammatory cells into ischemic tissues as well as numbers of inflammatory cells and endothelial progenitor cells (c-kit+/CD31+ cells) in both peripheral blood and bone marrow (BM) are significantly reduced in these knockout mice. Of note, ecSOD expression is markedly increased in BM after ischemia. NO2-/NO3- and cGMP levels are decreased in ecSOD(-/-) BM. Transplantation of wild-type BM into ecSOD(-/-) mice rescues the defective neovascularization. Thus, ecSOD in BM and ischemic tissues induced by hindlimb ischemia may represent an important compensatory mechanism that blunts the overproduction of O2-, which may contribute to reparative neovascularization in response to ischemic injury.
Kim
Ha Won
HW
Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Lin
Angela
A
Guldberg
Robert E
RE
Ushio-Fukai
Masuko
M
Fukai
Tohru
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D005110:Extracellular Space / Q000201:enzymology; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D013234:Stem Cells / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology
D000975:Antioxidants; D003497:Cyclic N-Oxides; D009566:Nitrates; D009573:Nitrites; D017382:Reactive Oxygen Species; D013113:Spin Labels; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D006152:Cyclic GMP; C001803:tempol