Journal Article

Hypoxia Differentially Regulates Arterial and Venous Smooth Muscle Cell Migration

Chanakira, Alice, Ramakrishnan, Sundaram, Kir, Devika, Roy, Sabita, Santilli, Steve M., Barke, Roderick A.

2015

Overview

Intimal hyperplasia (IH) is a clinical concern leading to failure of up to 50% of vein grafts and 10% of arterial grafts after 10 years with no known current treatment. Recent studies have shown that hypoxia differentially regulates proliferation of vein derived smooth muscle cells (V-SMC) compared to artery derived smooth muscle cells (A-SMC). The objective of this study is to evaluate the effect of hypoxia on cellular migration and the mechanisms underlying the differential effects of hypoxia on A-SMC and V-SMC migration. Hypoxic treatment (3-5% O2) of Smooth Muscle Cells (SMC) resulted in differential migration in scratch wound and electric cell substrate impedance sensing (ECIS) assays. Hypoxia led to greater migration compared to normoxia with venous derived wound closure (V-SMC 30.8% Normoxia to 67% Hypoxia) greater than arterial wound closure (A-SMC 6.2% Normoxia to 24.7% Hypoxia). Paracrine factors secreted by hypoxic endothelial cells induced more migration in SMC compared to factors secreted by normoxic endothelial cells. Migration of V-SMC was greater than A-SMC in the presence of paracrine factors. Neutralizing antibody to Vascular Endothelial Growth Factor Receptor -1 (VEGFR-1) completely inhibited V-SMC migration while there was only partial inhibition of A-SMC migration. A-SMC migration was completely inhibited by Platelet Derived Growth Factor BB (PDGF-BB) neutralizing antibody. p38 Mitogen Activated Protein kinase (p38 MAPK) inhibitor pre-incubation completely inhibited migration induced by paracrine factors in both A-SMC and V-SMC. Our study determines that SMC migration under hypoxia occurs via both an autocrine and paracrine mechanism and is dependent on Vascular Endothelial Growth Factor-A (VEGF-A) in V-SMC and PDGF-BB in A-SMC. Migration of both A-SMC and V-SMC is inhibited by p38 MAPK inhibitor. These studies suggest that pharmacotherapeutic strategies directed at modulating p38 MAPK activity can be exploited to prevent IH in vascular grafts.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Arteries - metabolism / Arteriosclerosis / Autocrine signalling / Cardiology / Cardiovascular disease / Care and treatment / Cell adhesion & migration / Cell culture / Cell growth / Cell Hypoxia - physiology / Cell migration / Cell Movement - physiology / Cell proliferation / Coronary artery bypass / Coronary heart disease / Coronary restenosis / Coronary vessels / Endothelial cells / Enzyme inhibitors / Grafting / Grafts / Health aspects / Heart / Humans / Hyperplasia / Hypoxia / Immunoglobulins / Inhibitors / Kinases / MAP kinase / Muscle, Smooth, Vascular - cytology / Muscle, Smooth, Vascular - metabolism / Muscles / Myocytes, Smooth Muscle - cytology / Myocytes, Smooth Muscle - metabolism / Neutralizing / p38 Mitogen-Activated Protein Kinases - metabolism / Paracrine signalling / Pharmacology / Phosphorylation / Physiology / Platelet-derived growth factor / Platelet-derived growth factor BB / Protein kinase / Risk factors / Smooth muscle / Substrates / Thoracic surgery / Thrombosis / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-1 - metabolism / Vascular endothelial growth factor receptors / Vascular surgery / Veins - metabolism / Wounds