title: PI-3K/AKT signal pathway modulates vascular smooth muscle cells migration under cyclic mechanical strain.
abstract: BACKGROUND
  The migration of vascular smooth muscle cells (VSMCs), exposed to altered mechanical strain, contributes to vascular remodeling which is the key event underlying the pathogenesis of vascular diseases such as atherosclerosis and restenosis. Signal transduction pathways in VSMCs activated by mechanical strain that influence cell migration remain unclear. Herein, we provide evidence that higher mechanical strain enhances VSMCs migration, which is mediated, at least in part, through Akt/protein kinase B (PKB) included pathway.
  
  
  METHODS
  VSMCs were exposed to mechanical strain at 15 % elongation and 5 % elongation, 60 cycles/min using FX-4000T system from at least three independent experiments. VSMCs were incubated with 100nmol/L wortmannin, 10 uM Akti, 10 uM PD98059 and 10 uM SB202190 prior to strain for inhibitor studies, respectively. VSMCs migration,the activation of Akt/PKB, the inhibition of STI-571 and immunofluorescence for actin fibers were detected, respectively. Activation of the Akt pathway and inhibition of STI-571 were assessed with the Western blot technique.
  
  
  RESULTS
  (1) Our study demonstrated that VSMCs migration under 15 % strain was facilitated compared with 5 % strain (15 % strain vs. 5 % strain, P < 0.01); and the activation of P-Akt was enhanced compared to the control (15 % strain and 5 % strain vs. static control, P < 0.01, respectively); whereas wortmannin could markedly inhibit serine/threonine kinase Akt/PKB phosphorylation, reduced VSMCs migration following higher mechanical strain stimulation (15 % strain + wortmannin vs. 15 % strain, P < 0.01). Immunofluorescence revealed actin rearrangement, which could also be inhibited by wortmannin in VSMCs induced by cyclic strain. (2) Akti significantly inhibited VSMCs migration (15 % strain + Akti and 5 % strain + Akti vs. static control, P < 0.05,respectively), neither PD98059 nor SB202190 inhibited VSMCs migration (5 % strain + PD98059 or +SB202190 vs. static control, P < 0.01; 15 % strain + PD98059 or +SB202190 vs. static control P < 0.01,respectively). (3) Higher mechanical strain inhibits STI-571 activity in VSMCs (5 % strain vs. static control, P < 0.05; 15 % strain vs. static control, P < 0.01).
  
  
  CONCLUSIONS
  Our data shows that higher mechanical strain activated-Akt/PKB is required for VSMC migration and probably functions through its effects on actin rearrangement.
authors.affiliation: Department of Cardiology, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: B-C
authors.initials: BC
authors.lastname: Zhang
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Zhou
authors.forename: X-K
authors.initials: XK
authors.lastname: Li
authors.forename: Y-W
authors.initials: YW
authors.lastname: Xu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D000199:Actins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt