Shear stress downregulation of platelet-derived-growth factor receptor- β and matrix metalloprotease-2 is associated with inhibition of smooth muscle cell invasion and migration

Abstract

Background - After endovascular injury, smooth muscle cells (SMCs) may be exposed to hemodynamic shear stress (SS), and these forces modulate neointima accumulation. The effect of SS on SMC migration and invasion is unknown, and it was examined in the present study. Methods and Results - Bovine aortic SMCs were exposed to laminar SS of 12 dyne/cm2 for 3 (SS3) or 15 (SS15) hours; control (C3 and C15) SMCs were kept under static conditions. Platelet-derived growth factor (PDGF)-BB-directed SMC migration and invasion were evaluated by a modified Boyden chamber assay with filters coated with either gelatin or reconstituted basement membrane proteins (Matrigel), respectively. SS15 inhibited both SMC migration and invasion (P<0.0001). There was no significant difference between SS3 and C3 cells. Media conditioned with SS15 cells exhibited a reduction in matrix metalloprotease-2 (MMP-2) by zymography and Western analysis. Northern blot analysis revealed no effect of SS15 on MMP-2 mRNA. In contrast, SS15 decreased MMP-2 activator and membrane-type MMP (MT-MMP or MMP-14) mRNA and protein. Furthermore, SS15 decreased PDGF receptor-β (PDGF-Rβ) mRNA and protein (P<0.05), and the SS- dependent decrease in PDGF-BB-directed cell migration was rescued by overexpressing PDGF-Rβ. Conclusions - SS inhibits SMC migration and invasion via diminished PDGF-Rβ expression. This effect of SS is associated with decreased MMP-2 secretion and MT-MMP downregulation.