Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 -L680, 2014. First published September 19, 2014 doi:10.1152/ajplung.00198.2014.-Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca 2ϩ channels, increased intracellular Ca 2ϩ, and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation. lung ischemia; ischemia-reperfusion; lung transplantation; mechanotransduction; reactive oxygen species; K ATP channel; NADPH oxidase; lung perfusion and storage; EVLP THE RELATED TERMS mechanosensing, mechanosignaling, and mechanotransduction refer to the sensing of physical forces by cells and their translation into a biochemical response, analogous to the processes termed chemotransduction. Among the various physical forces to which cells in vivo are constantly exposed, mechanical stimuli associated with blood flow are particularly important. Indeed, fluid shear stress and distending pressure that act on the vessel wall play a major role in vascular homeostasis. The vascular endothelium, by virtue of its location, serves as an interface between the blood and tissue for hemodynamic changes. Recent work demonstrates that the endothelium senses and integrates hemodynamic stimuli including shear to effect maintenance of vascular function and possibly modulate the onset of vascular disease. The currently accepted paradigm is that "sensing" of a change (either increa...