Shear stress as an inhibitor of vascular smooth muscle cell proliferation. Role of transforming growth factor-beta 1 and tissue-type plasminogen activator

Abstract

We examined whether shear stress can inhibit vascular smooth muscle cell (VSMC) proliferation in vitro directly. Human VSMCs were exposed to fluid flow for 24 hours using a cone-plate apparatus, and their proliferation was inhibited significantly by shear stresses of 1.4 and 2.8 Pa (14 and 28 dyne/cm2), according to the magnitude. Next, we investigated whether transforming growth factor-beta 1 (TGF beta 1), which is known to be an important cytokine that suppresses VSMC proliferation, is the predominant mediator of shear-induced inhibition of VSMC growth. After exposure of VSMCs to shear stress (2.8 Pa) for 24 hours, gene 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 both latent and active forms of TGF beta 1 in conditioned media of VSMCs exposed to fluid flow increased significantly. An anti-TGF beta 1 antibody reversed shear-induced inhibition of VSMC growth significantly. We concluded that shear stress inhibited VSMC proliferation in vitro and this inhibition was mediated predominantly by TGF beta 1 in an autocrine manner. These data suggest that shear stress plays an important role as an inhibitor of atherogenesis in endothelium-desquamated lesions.