Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β ₁ -Integrin Signaling Pathways

Abstract

Abstract-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 ␤ 1 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 ␤ 1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a ␤ 1 -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 ␤ 1 -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 ␤ 1 -integrin-rac-p38-p53 signaling pathways.

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

“…This results in low, oscillating, or reversing shear stress, which in turn leads to atherosclerosis and vascular calcification 30, 31. VSMCs sense the disturbed wall shear stress and pressure distension caused by intravascular and interstitial fluid overload through membrane mechanoreceptors, and activate the signaling pathways such as small guanosine triphosphatase related to Ras A (RhoA)/Rho‐associated protein kinase, mitogen‐activated protein kinase, phosphatidylinositol‐3‐kinase/protein kinase B, and extracellular signal‐regulated kinase 32, 33, 34. These signaling pathways induce the proliferation, migration, apoptosis, and osteoblastic differentiation of VSMCs, and altered VSMCs play a major role in vascular calcification 35, 36.…”

Integrins in Mechanotransduction

“…In vascular smooth muscle cells, cyclic strain stimulated mitogenesis through integrin ␣ v ␤ 3 -dependent release of plateletderived growth factor (46). Cyclic stretch of vascular smooth muscle cells increased apoptosis of cells on collagen I, but not on other matrixes, and this effect was mediated by a pathway involving Rac, p38 MAP kinase, and p53 (40). Smooth muscle contraction was inhibited by brief pretreatment with RGD peptides that bind ␣ v ␤ 3 and ␣ 5 ␤ 1 integrins (47).…”

“…Classical studies of cellular responses to mechanical forces have demonstrated that fibroblasts, smooth muscle cells, and cardiac myocytes orient in response to cyclic stretch, although the direction of alignment can be either parallel or perpendicular to the direction of stretch depending on the cell type (3, 4). Externally applied strain also influences cell growth and survival (4,39,40). In all of the in vitro systems, forces are by definition transmitted through cell contacts with the substratum, thereby implicating integrins in mechanotransduction.…”

Substrate-induced phenotypic switches of human smooth muscle cells: anin vitrostudy of in-stent restenosis activation pathways

“…The role played by SMCs in vascular complications has been widely investigated, with research focusing on mechanical stimuli, (ECM) protein adhesion and cell behaviour [11][12][13][14]. In particular, the SMCs ability to proliferate and produce HA has been closely examined.…”