Long-term cyclic stretch controls pulmonary endothelial permeability at translational and post-translational levels

Abstract

We have previously described differential effects of physiologic (5%) and pathologic (18%) cyclic stretch (CS) on agonist-induced pulmonary endothelial permeability. This study examined acute and chronic effects of CS on agonist-induced intracellular signaling and cell morphology in the human lung macro-and microvascular endothelial cell (EC) monolayers. Endothelial permeability was assessed by analysis of morphological changes, parameters of cell contraction and measurements of transendothelial electrical resistance. Exposure of both microvascular and macrovascular EC to 18% CS for 2 -96 hrs increased thrombin-induced permeability and monolayer disruption. Interestingly, the ability to promote thrombin responses was present in EC cultures exposed to 48-96 hrs of CS even after replating onto non-elastic substrates. In turn, physiologic CS preconditioning (72 hrs) attenuated thrombin-induced paracellular gap formation and MLC phosphorylation in replated EC cultures. Long term preconditioning at 18% CS (72 hrs) increased the content of signaling and contractile proteins including Rho GTPase, MLC, MLC kinase, ZIP kinase, PAR1, caldesmon and HSP27 in the pulmonary microvascular and macrovascular cells. We conclude that short term CS regulates EC permeability via modulation of agonist-induced signaling, whereas long term CS controls endothelial barrier at both post-translational level and via magnitude-dependent regulation of pulmonary EC phenotype, signaling and contractile protein expression.

Activation of Vascular Endothelial Growth Factor (VEGF) Receptor 2 Mediates Endothelial Permeability Caused by Cyclic Stretch

“…*, p Ͻ 0.05 versus ns-RNA. stretch and flow preconditioning have been described in the literature (55)(56)(57). Altogether, changing set points of sensitivity to circulating agonists by organ or vessel exposure to physiologic or pathologic mechanical forces may be an important factor defining specific responses to external stimuli.…”

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

“…Exogenous mechanical forces such as fluid shear stress and the stiffness of the lamina intima also regulate vascular function [1–4], and promote extracellular matrix (ECM) deposition and cross linking [5]. In vitro , physiological cyclic strain further coordinates with matrix stiffness to protect endothelial junctions against disruption by vasoactive agents such as thrombin [3,4,6]. …”

Mechanical induction of group V phospholipase A2causes lung inflammation and acute lung injury

“…Nearly all patients with ARDS require mechanical ventilation and are therefore at risk for ventilatorinduced lung injury (VILI), which appears to be due in part to the uneven distribution of mechanical distension and lung injury in ARDS. Similarly to mechanically ventilated lungs, pathologically relevant levels of cyclic stretch (CS) applied to endothelial cell (EC) monolayers in vitro lead to exacerbation of agonist-induced endothelial barrier dysfunction, thus representing the two-hit model of VILI (5)(6)(7)24).…”