CYBB and ischemia: In parallel, and importantly in lungs even when parenchymal oxygenation is preserved, ischemia alters endothelial shear sensing: stop-of-flow is detected by a caveolae-resident “mechanosome” (PECAM-1/VEGFR2/VE-cadherin), leading to KATP-channel closure, endothelial depolarization, opening of T-type Ca2+ channels and eNOS activation, and phosphoinositide 3-kinase (PI3K)–Akt–dependent assembly of NOX2 with ROS generation; the abrupt change in shear on reperfusion can further activate NOX2.