Glutaredoxin overexpression inhibits angiogenesis in vivo through regulation of soluble VEGFR1

Abstract

Glutaredoxin‐1 (Glrx) catalyzes the reduction of protein mixed disulfides (PSSG) and regulates function of proteins with redox‐sensitive thiols. We used Glrx transgenic (Tg) mice to investigate the role of Glrx overexpression on angiogenesis in vivo. Tg mice had impaired blood flow recovery and lower clinical function scores in an in vivo model of hind limb ischemia (HLI). VEGF‐induced aortic spouting and endothelial cell (EC) tube formation were attenuated in aortae and EC isolated from Tg mice. Interestingly, we observed an increase in soluble FLT (sFLT/sVEGFR1), the anti‐angiogenic VEGF receptor in Tg mouse plasma post‐HLI and media from Tg ECs. In addition, Glrx overexpression increased the non‐canonical Wnt ligand, Wnt5a, in both ischemic muscle and EC. Furthermore, Glrx induced‐sFLT1 expression in endothelial cells was attenuated by Box5, a competitive inhibitor of Wnt5a. Together these data suggest that Glrx overexpression negatively regulates angiogenesis post‐hind limb ischemia by regulating VEGF signaling through Wnt5a‐sFLT pathway. We speculate that enhanced Glrx expression may be critical to impaired angiogenesis observed in pathological conditions. (R37 HL104017 and PO1HL068758)