Journal Article

Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis

Segarra, Marta, Preciado, Sara, Lavilla, Rodolfo, Lozano, Ester, Cid, Maria C, Alba, Marco A, Planas-Rigol, Ester, Prieto-González, Sergio, Hernández-Rodríguez, José, Corbera-Bellalta, Marc, Espígol-Frigolé, Georgina, Terrades-Garcia, Nekane

2017

Overview

BackgroundGiant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function.ObjectiveTo investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA.Methods and resultsImmunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ETBR), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ETBR antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants.ConclusionsET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA.

• Publisher: Elsevier Limited,BMJ Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / Actin / Actins - drug effects / Actins - genetics / Actins - metabolism / Aged / Arteries / Arteritis / Arteritis de cèl·lules gegants / Autoimmune diseases / Blotting, Western / Case-Control Studies / Cell activation / Cell adhesion & migration / Cell migration / Cell Movement - drug effects / Cell Movement - genetics / Confocal microscopy / Endothelin 1 / Endothelin Receptor Antagonists - pharmacology / Endothelin-1 - genetics / Endothelin-1 - metabolism / Endothelin-1 - pharmacology / Explants / Female / Fluorescent Antibody Technique / Focal adhesion kinase / Focal Adhesion Kinase 1 - antagonists & inhibitors / Focal Adhesion Kinase 1 - metabolism / Giant cell arteritis / Giant Cell Arteritis - genetics / Giant Cell Arteritis - metabolism / Giant Cell Arteritis - pathology / Humans / Hyperplasia / Immunofluorescence / In Vitro Techniques / Kinases / Leukocytes, Mononuclear / Malalties vasculars / Male / Microscopy, Confocal / Muscle, Smooth, Vascular - cytology / Muscle, Smooth, Vascular - metabolism / Myocytes, Smooth Muscle - cytology / Myocytes, Smooth Muscle - drug effects / Myocytes, Smooth Muscle - metabolism / Occlusion / Phosphatidylinositol 3-Kinases - metabolism / Phosphoinositide-3 Kinase Inhibitors / Phosphorylation / Receptor, Endothelin A - drug effects / Receptor, Endothelin A - metabolism / Receptor, Endothelin B - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Smooth muscle / Src protein / src-Family Kinases - metabolism / Tunica Intima - pathology / Vascular diseases / Vascular Remodeling - drug effects / Vascular Remodeling - genetics / Vasoactive agents / Vein & artery diseases / Veins & arteries