Fig. 7. Proposed pathways for mechanotransduction with lung ischemia.

Loss of shear stress due to flow cessation is sensed by the endothelial cells, presumably via caveolae. K_ATP channels which are predominantly localized in caveolae are deactivated with ischemia. Closure of this channel causes endothelial membrane depolarization that leads to activation of NADPH oxidase. This occurs via PI3 kinase activation that causes rac translocation to the endothelial plasma membrane. These cause NADPH oxidase assembly resulting in generation of reactive oxygen species (ROS). The decreased membrane potential due to K⁺-channel “closure” opens voltage gated Ca²⁺ channels (VGCC) that allows for Ca²⁺ influx resulting in activation of endothelial NO synthase and NO generation. The cell signaling cascade results in endothelial cell proliferation. NO generation and cell proliferation might represent mechanisms to restore blood flow.