Mechanotransduction Drives Post Ischemic Revascularization Through KATP Channel Closure and Production of Reactive Oxygen Species

Aims: We reported earlier that ischemia results in the generation of reactive oxygen species (ROS) via the closure of a K-ATP channel which causes membrane depolarization and NADPH oxidase 2 (NOX2) activation. This study was undertaken to understand the role of ischemia-mediated ROS in signaling. Results: Angiogenic potential of pulmonary microvascular endothelial cells (PMVEC) was studied in vitro and in the hind limb in vivo. Flow adapted PMVEC injected into a Matrigel matrix showed significantly higher tube formation than cells grown under static conditions or cells from mice with knockout of K-ATP channels or the NOX2. Blocking of hypoxia inducible factor-1 alpha (HIF-1) accumulation completely abrogated the tube formation in wild-type (WT) PMVEC. With ischemia in vivo (femoral artery ligation), revascularization was high in WT mice and was significantly decreased in mice with knockout of K-ATP channel and in mice orally fed with a K-ATP channel agonist. In transgenic mice with endothelial-specific NOX2 expression, the revascularization observed was intermediate between that of WT and knockout of K-ATP channel or NOX2. Increased HIF-1 activation and vascular endothelial growth factor (VEGF) expression was observed in ischemic tissue of WT mice but not in K-ATP channel and NOX2 null mice. Revascularization could be partially rescued in K-ATP channel null mice by delivering VEGF into the hind limb. Innovation: This is the first report of a mechanosensitive ion channel (K-ATP channel) initiating endothelial signaling that drives revascularization. Conclusion: The K-ATP channel responds to the stop of flow and activates signals for revascularization to restore the impeded blood flow.