title: Hypoxia Differentially Regulates Arterial and Venous Smooth Muscle Cell Migration.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, United States of America.
authors.forename: Alice
authors.initials: A
authors.lastname: Chanakira
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, United States of America; Department of Pharmacology, University of Minnesota, Minneapolis, United States of America.
authors.forename: Devika
authors.initials: D
authors.lastname: Kir
authors.affiliation: VA Medical Center, Minneapolis, Minnesota, United States of America.
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Barke
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, United States of America; VA Medical Center, Minneapolis, Minnesota, United States of America.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Santilli
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, United States of America.
authors.forename: Sundaram
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, United States of America; Department of Pharmacology, University of Minnesota, Minneapolis, United States of America.
authors.forename: Sabita
authors.initials: S
authors.lastname: Roy
mesh_terms: D001158:Arteries / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014680:Veins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases