Shear stress-induced restoration of pulmonary endothelial barrier function following ischaemia reperfusion injury requires VEGFR2 signalling

Abstract

Normal physiological shear stress produced by blood flow is sensed by the vascular endothelium and required for the maintenance of both the normal structure and barrier function of the endothelium. Many common, critical illnesses are characterised by periods of abnormally reduced or absent shear stress e.g. haemorrhagic shock, myocardial infarction and pulmonary embolism and are complicated by oedema formation following restoration of normal perfusion (IRI). We tested the hypothesis that, in lungs injured by a period of ischaemia and reperfusion (IRI), reduced shear stress contributes to increased endothelial barrier permeability and oedema formation following the restoration of perfusion. Furthermore, we examined the role of VEGFR2 as a mechanosensor in the response of the pulmonary endothelium to altered shear stress in this condition. 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 shear stresses on the endothelium of the intact pulmonary circulation. Lungs perfused with LVS developed pulmonary oedema due to increased endothelial permeability whereas those perfused with PVS were protected from oedema formation by reduced endothelial permeability. This effect of PVS required normal VEGFR2 tyrosine kinase activity but was unaffected by blocking VEGFA binding to the receptor. These data show for the first time that shear stress has an important role in restoring endothelial barrier function in the pulmonary circulation following injury and have important implications for the treatment of pulmonary oedema in critically ill patients following ischaemia reperfusion injury.