title: Magnitude-dependent effects of cyclic stretch on HGF- and VEGF-induced pulmonary endothelial remodeling and barrier regulation.
abstract: Mechanical ventilation at high tidal volumes compromises the blood-gas barrier and increases lung vascular permeability, which may lead to ventilator-induced lung injury and pulmonary edema. Using pulmonary endothelial cell (ECs) exposed to physiologically [5% cyclic stretch (CS)] and pathologically (18% CS) relevant magnitudes of CS, we evaluated the potential protective effects of hepatocyte growth factor (HGF) on EC barrier dysfunction induced by CS and vascular endothelial growth factor (VEGF). In static culture, HGF enhanced EC barrier function in a Rac-dependent manner and attenuated VEGF-induced EC permeability and paracellular gap formation. The protective effects of HGF were associated with the suppression of Rho-dependent signaling triggered by VEGF. Five percent CS promoted HGF-induced enhancement of the cortical F-actin rim and activation of Rac-dependent signaling, suggesting synergistic barrier-protective effects of physiological CS and HGF. In contrast, 18% CS further enhanced VEGF-induced EC permeability, activation of Rho signaling, and formation of actin stress fibers and paracellular gaps. These effects were attenuated by HGF pretreatment. EC preconditioning at 5% CS before HGF and VEGF further promoted EC barrier maintenance. Our data suggest synergistic effects of HGF and physiological CS in the Rac-mediated mechanisms of EC barrier protection. In turn, HGF reduced the barrier-disruptive effects of VEGF and pathological CS via downregulation of the Rho pathway. These results support the importance of HGF-VEGF balance in control of acute lung injury/acute respiratory distress syndrome severity via small GTPase-dependent regulation of lung endothelial permeability.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA. kbirukov@medicine.bsd.uchicago.edu
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
authors.forename: Nurgul
authors.initials: N
authors.lastname: Moldobaeva
authors.forename: Junjie
authors.initials: J
authors.lastname: Xing
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008465:Mechanoreceptors / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics
chemical_list: D000199:Actins; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins