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(Circulation Research. 2007;101:409.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Essential Role of Extracellular SOD in Reparative Neovascularization Induced by Hindlimb Ischemia

Ha Won Kim, Angela Lin, Robert E. Guldberg, Masuko Ushio-Fukai^*, Tohru Fukai^*

From the Departments of Medicine and Pharmacology (H.W.K., T.F.) and the Department of Pharmacology (M.U.-F.), University of Illinois at Chicago; and the Woodruff School of Mechanical Engineering (A.L., R.G.), Georgia Institute of Technology, Atlanta.

Correspondence to Tohru Fukai, MD, PhD, Departments of Medicine and Pharmacology, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403 MSB, Chicago, IL 60612. E-mail tfukai{at}uic.edu; and Masuko Ushio-Fukai, PhD, Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403 MSB, Chicago, IL 60612. E-mail mfukai@uic.edu

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.

Key Words: superoxide dismutase • reactive oxygen species • neovascularization • bone marrow • endothelial progenitor cells

Related Article:

ecSOD Controls the Delicate Balance of Reactive Oxygen Species in Bone Marrow and Ischemic Tissue Needed for Neovascularization

Michael S. Wolin
Circ. Res. 2007 101: 331-332. [Extract] [Full Text] [PDF]

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