Shear stress-induced restoration of pulmonary microvascular endothelial barrier function following ischemia reperfusion injury requires VEGFR2 signaling.

Abstract

Normal shear stress produced by blood flow is sensed by the vascular endothelium and required for maintenance of the homeostatic functions of the endothelium in systemic conduit and resistance vessels. Many critical illnesses are characterized by periods of abnormally reduced or absent shear stress in the lung (e.g., hemorrhagic shock, embolism, ischemia reperfusion injury, and lung transplantation) and are complicated by pulmonary edema following reperfusion due to microvascular leak. The role of shear stress in regulating the pulmonary microvascular endothelial barrier in the intact vascular bed has not been previously examined. We tested the hypothesis that, in lungs injured by a period of ischemia and reperfusion (IRI), reduced shear stress contributes to increased pulmonary microvascular endothelial barrier permeability and edema formation. Furthermore, we examined the role of vascular endothelial-derived growth factor receptor 2 (VEGFR2) as a mechanosensor mediating the endothelial response to this altered shear stress. Following IRI, we perfused isolated ventilated mouse lungs with a low viscosity solution (LVS) or a higher, physiological viscosity solution (PVS) at constant flow to produce differing endothelial shear stresses in the intact microcirculation. Lungs perfused with LVS developed pulmonary edema due to increased endothelial permeability whereas those perfused with PVS were protected from edema formation by reduced endothelial permeability. This effect of PVS required normal VEGFR2 mechanoreceptor function. These data show for the first time that shear stress has an important role in restoring endothelial barrier function in the intact pulmonary microcirculation following injury and have important implications for the treatment of pulmonary edema in critically ill patients.NEW & NOTEWORTHY Critical illnesses are frequently complicated by noncardiogenic pulmonary edema. Many such illnesses include periods of reduced blood flow, often accompanied by hemodilution, which together reduce endothelial shear stress. We report that in ischemia-reperfusion injury reduced shear stress contributes to increased permeability of the in situ pulmonary microvascular endothelium and worsens alveolar edema. Restoring shear stress toward normal reduces endothelial permeability and edema formation, an effect that requires the normal mechanoreceptor function of VEGFR2.