title: Negative regulation of vascular smooth muscle cell migration by blood shear stress.
abstract: Vortex blood flow with reduced blood shear stress in a vein graft has been hypothesized to promote smooth muscle cell (SMC) migration and intimal hyperplasia, pathological events leading to vein graft restenosis. To demonstrate that blood shear stress regulates these processes, we developed a modified vein graft model where the SMC response to reduced vortex blood flow was compared with that of control vein grafts. Vortex blood flow induced SMC migration and neointimal hyperplasia in control vein grafts, whereas reduction of vortex blood flow in the modified vein graft strongly suppressed these effects. A venous polymer implant with known fluid shear stress was employed to clarify the molecular mechanism of shear-dependent SMC migration in vivo. In the polymer implant, the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and myosin light chain kinase (MLCK), found primarily in SMCs, increased from day 3 to day 5 and returned toward the control level from day 5 to day 10, with the peak phosphorylation associated with the maximal speed of SMC migration. Treatment with PD-98059 (an inhibitor specific to the ERK1/2 activator MEK1/2) significantly suppressed the phosphorylation of MLCK, suggesting a role for ERK1/2 in regulating the activity of MLCK. Treatment with PD-98059 or ML-7 (an inhibitor specific to MLCK) reduced shear stress-dependent SMC migration, resulting in an SMC distribution independent of fluid shear stress. These results suggest that fluid shear stress regulates SMC migration via the mediation of ERK1/2 and MLCK.
authors.affiliation: Biomedical Engineering Department, Michigan Technological University, Houghton, MI 49931, USA. jgoldman@mtu.edu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Goldman
authors.forename: Lin
authors.initials: L
authors.lastname: Zhong
authors.forename: Shu Q
authors.initials: SQ
authors.lastname: Liu
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D019917:Blood Vessel Prosthesis Implantation; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000503:physiopathology*; D006965:Hyperplasia; D007601:Jugular Veins / Q000637:transplantation; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011673:Pulsatile Flow; D051381:Rats; D017207:Rats, Sprague-Dawley; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D009219:Myosin-Light-Chain Kinase; D048049:Extracellular Signal-Regulated MAP Kinases