Abstract

Mechanotransduction plays a prominent role in vascular pathophysiology but is incompletely understood. In this study, we report the biomechanical induction of the immediate early response gene iex-1 in vascular smooth muscle cells (SMCs). Mechanical induction of iex-1 was confirmed by Northern (30-fold induction after 2 hours) and Western (6-fold induction after 24 hours) analyses. Expression of iex-1 was regulated by mechanical activation of nuclear factor (NF)-kappaB and abolished by overexpression of IkappaB in SMCs. The function of iex-1 in SMCs was explored by gene transfer using adenoviral vectors overexpressing iex-1. After 48 hours of 4% cyclic mechanical strain, adenoviral vectors overexpressing iex-1-infected cells had lower 3[H]-thymidine incorporation compared with AdGFP-infected controls (71.3+/-8.5% versus 180.2+/-19.4% in controls; P<0.001). Overexpression of iex-1 suppressed mitogenesis induced by platelet-derived growth factor (208.1+/-108.3% versus 290.0+/-120.5% in controls; P<0.05). This was accompanied by reduced degradation of p27kip1, inhibition of Rb hyperphosphorylation, and reduced cell cycle progression. To investigate functional effects of iex-1 in vivo, we performed carotid artery mechanical injury and endothelial denudation in low-density lipoprotein receptor-deficient mice followed by intraluminal injection of adenoviral vectors (3x10(9) pfu in 50 microL) for overexpression of iex-1 or gfp (control). Vascular overexpression of iex-1 reduced neointima formation 2 weeks after injury (intima/media ratio, 0.23+/-0.04 versus 0.5+/-0.24 in controls; P<0.05). Our findings demonstrate that biomechanical strain induces iex-1 with subsequent antiproliferative effects in SMCs and that selective gene transfer of iex-1 inhibits the local vascular response after injury. These findings suggest that the induction of iex-1 represents a novel negative biomechanical feedback mechanism limiting the vascular response to injury.