Affiliations: Inserm, U955, E13, Biomécanique Cellulaire et Respiratoire, Créteil, France | CNRS, ERL 7240, Créteil, France | Université Paris Est, Faculté de Médecine, Créteil, France | Department of Anesthesiology, the First Affiliated Hospital, Chongqing Medical University, China | AP-HP, Hôpital Henri Mondor–Albert Chenevier, Physiologie, Créteil, France
Note: [] The two first authors have contributed equally.
Note: [] Address for correspondence: Daniel Isabey, Inserm UMR955, IMRB, Cell and Respiratory Biomechanics Department (E13), 8, rue du Général Sarrail, Créteil 94010, France. Tel.: +33 149 81 37 00; Fax: +33 148 98 17 77; E-mail: daniel.isabey@inserm.fr.
Abstract: Mechanical factors play a key role in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) as contributing to alveolo-capillary barrier dysfunction. This study aims at elucidating the role of the cytoskeleton (CSK) and cell–matrix adhesion system in the stressed endothelium and more precisely in the loss of integrity of the endothelial barrier. We purposely develop a cellular model made of a monolayer of confluent Human Pulmonary Microvascular Endothelial Cells (HPMVECs) whose cytoskeleton (CSK) is directly exposed to sustained cyclic mechanical stress for 1 and 2 h. We used RGD-coated ferromagnetic beads and measured permeability before and after stress application. We find that endothelial permeability increases in the stressed endothelium, hence reflecting a loss of integrity. Structural and mechanical results suggest that this endothelial barrier alteration would be due to physically-founded discrepancies in latero-basal reinforcement of adhesion sites in response to the global increase in CSK stiffness or centripetal intracellular forces. Basal reinforcement of adhesion is presently evidenced by the marked redistribution of αvβ3 integrin with cluster formation in the stressed endothelium.
