SHEAR-STRESS AS AN INHIBITOR OF VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION - ROLE OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND TISSUE-TYPE PLASMINOGEN-ACTIVATOR

We examined whether shear stress can inhibit vascular smooth muscle ce ll (VSMC) proliferation in vitro directly. Human VSMCs were exposed to fluid flow for 24 hours using a cone-plate apparatus, and their proli feration was inhibited significantly by shear stresses of 1.4 and 2.8 Pa (14 and 25 dyne/cm(2)), according to the magnitude. Next, we invest igated whether transforming growth factor-beta 1 (TGF beta 1), which i s known to be an important cytokine that suppresses VSMC proliferation , is the predominant mediator of shear-induced inhibition of VSMC grow th. After exposure of VSMCs to shear stress (2.8 Pa) for 24 hours, gen e expression of TGF beta 1 and, interestingly, tissue-type plasminogen activator, which converts plasminogen to plasmin; an activator of TGF beta 1, increased twofold and fivefold, respectively. The levels of b oth latent and active forms of TGF beta 1 in conditioned media of VSMC s exposed to fluid flow increased significantly. An anti-TGF beta 1 an tibody reversed sheer-induced inhibition of VSMC growth significantly. We concluded that sheer stress inhibited VSMC proliferation in vitro and this inhibition was mediated predominantly by TGF beta 1 in an aut ocrine manner. These data suggest that sheer stress plays an important role as an inhibitor of atherogenesis in endothelium-desquamated lesi ons.