Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia

• Published in: PloS one Vol. 10; no. 9; p. e0138847
• Main Authors: Longchamp, Alban, Allagnat, Florent, Alonso, Florian, Kuppler, Christopher, Dubuis, Céline, Ozaki, Charles-Keith, Mitchell, James R, Berceli, Scott, Corpataux, Jean-Marc, Déglise, Sébastien, Haefliger, Jacques-Antoine
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.09.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Arteriosclerosis; Atherosclerosis; Biology; Carotid arteries; Cell Proliferation; Cell signaling; Connexin 43; Connexin 43 - antagonists & inhibitors; Connexin 43 - physiology; Connexins; DNA microarrays; Genetic aspects; Grafting; Grafts; Hemodynamics; Humans; Hyperplasia; Hyperplasia - prevention & control; Implantation; Jugular vein; Laboratories; Male; Medicine; Membrane proteins; Muscle, Smooth, Vascular - pathology; Muscles; Perfusion; Physiological aspects; Physiology; Prevention; Public health; Rabbits; Ribonucleic acid; Risk factors; RNA; RNA-mediated interference; Shear stress; Smooth muscle; Thrombosis; Tunica Intima - pathology; Vascular Grafting; Vascular surgery; Veins; Veins & arteries; Veins - transplantation; Womens health; United States; Florida; United States > US; Switzerland; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0138847

Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment.