Tyrosine-kinase dependent TGF-beta and extracellular matrix expression by mechanical stretch in vascular smooth muscle cells

Vascular hypertrophy, which is characterized by proliferation of vascular s mooth muscle cells (VSMC) and accumulation of extracellular matrix(ECM), is a major pathological change in blood vessels after chronic exposure to hyp ertension. Blood pressure is transmitted to the arterial walls and counterb alanced by mechanical stress, leading to stretching of circumferentially or iented VSMC, which may play some role in the pathogenesis of vascular hyper trophy, The present study was designed, therefore, to investigate the effec t of mechanical stretch on the expression of ECM components and transformin g growth factor-beta (TGF-beta), a potent stimulator for ECM production, an d to examine the signal transduction mechanisms of the induction of TGF-bet a in cultured rat VSMC. VSMC were subjected to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles per minute for up to 24 h. Mechanical stretch stimulated TGF-beta 1 mRNA expression in a time- and el ongation-dependent manner. Indeed, the secretion of TGF-beta proteins into the culture media was increased after stretch. Stretch also stimulated mRNA expression of the ECM components, type I and type IV collagen, and fibrone ctin, which was largely inhibited by addition of neutralizing antibody agai nst TGF-beta. The tyrosine kinase inhibitors genistein and herbimycin A blo cked the induction of TGF-beta 1 and type I collagen by stretch, while prot ein kinase C inhibitors, the calcium channel blockers nitrendipine and gado linium, or Ca removal from the media had no effect. These results suggest t hat stretch induced, tyrosine kinase mediated autocrine/paracrine productio n of TGF-beta may play a critical role in the progression of vascular remod eling associated with high blood pressure. (Hypertens Res 2000; 23: 91-99).