We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1) and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1^-/- lungs as compared to lungs from wild type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT type pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1^-/- PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in wild type mice was significantly lowered in PECAM-1^-/- mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker, vascular endothelial growth factor (VEGF) as compared to untreated (sham) and PECAM-1^-/- lungs. Thus PECAM-1 (and caveolae) is part of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal.