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Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):E1137-45. doi: 10.1073/pnas.1104357108. Epub 2011 Sep 26.

Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2.

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Interdepartmental Program in Vascular Biology and Therapeutics, and Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.


Injury- and ischemia-induced angiogenesis is critical for tissue repair and requires nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS). We present evidence that NO induces angiogenesis by modulating the level of the angiogenesis inhibitor thrombospondin 2 (TSP2). TSP2 levels were higher than WT in eNOS KO tissues in hind-limb ischemia and cutaneous wounds. In vitro studies confirmed that NO represses TSP2 promoter activity. Moreover, double-eNOS/TSP2 KO mice were generated and found to rescue the phenotype of eNOS KO mice. Studies in mice with knock-in constitutively active or inactive eNOS on the Akt-1 KO background showed that eNOS activity correlates with TSP2 levels. Our observations of NO-mediated regulation of angiogenesis via the suppression of TSP2 expression provide a description of improved eNOS KO phenotype by means other than restoring NO signaling.

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