The role of KIR6.2 in mediating NOX2‐derived ROS‐dependent neovascularization in response to ischemic injury

Abstract

Acute ischemic injury results from vascular obstruction by pulmonary emboli and peripheral artery disease. Ischemia induces a burst of NADPH Oxidase 2 (NOX2)‐dependent endothelial reactive oxygen species (ROS) crucial for ischemia‐induced neovascularization. We have shown that KIR6.2 regulates NOX2‐derived ROS. An endothelial cell (EC) scratch assay indicated both NOX2‐and KIR‐null ECs migrate 50% slower than WT ECs. We hypothesize KIR6.2 is required for ROS‐mediated post‐ischemic neovascularization. KIR6.2‐and NOX2‐null, wild type (WT), Apocynin (Apo)‐ and Cromakalim (Crom)‐treated mice underwent femoral artery ligation. Doppler and fluorescent microbeads were used to detect macro‐ and microcirculation. NOX2‐and KIR6.2‐null and Crom‐and Apo‐treated mice have 65–80% fewer capillaries indicating reduced angiogenesis. KIR6.2‐null limbs are 35% less perfused at Day 5 but recover suggesting arteriogenesis is reduced less than angiogenesis. NOX2‐null mice have 30% and 25% less perfusion than WT at Days 14 and 21 suggesting that while NOX2‐derived ROS is important for angio‐and arteriogenesis, its regulation by KIR6.2 is crucial for angiogenesis. KIR6.2 contributes to the pathogenesis of diabetes‐related cardiovascular dysfunction thus the link between KIR6.2 and pro‐angiogenic ROS signaling has implications for treatment of diabetes‐related vascular complications. NHLBI‐T32‐S54932