Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways.
Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al. FASEB J. 2000;15:261-270). The current study was designed to investigate molecular mechanisms of mechanical stretch-induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I-coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin beta1 containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional Rac completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin beta1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a beta1-integrin-blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a beta1-integrin-blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress-induced apoptosis in vascular smooth muscle cells is mediated by beta1-integrin-rac-p38-p53 signaling pathways.
Wernig
Florian
F
Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK.
Mayr
Manuel
M
Xu
Qingbo
Q
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D011493:Protein Kinase C / Q000502:physiology; D051745:Protein Kinase C-delta; D051381:Rats; D015398:Signal Transduction; D013314:Stress, Mechanical; D013498:Suramin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000235:genetics
D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; D016159:Tumor Suppressor Protein p53; D003571:Cytochalasin B; D013498:Suramin; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins