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

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)409-419
Number of pages11
JournalCirculation research
Issue number4
StatePublished - Aug 2007
Externally publishedYes


  • Bone marrow
  • Endothelial progenitor cells
  • Neovascularization
  • Reactive oxygen species
  • Superoxide dismutase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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