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(Circulation Research. 2003;93:1210.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Biomechanically Induced Gene iex-1 Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation

P. Christian Schulze^*, Gilles W. de Keulenaer^*, Kimberly A. Kassik, Tomosaburo Takahashi, Zhiping Chen, Daniel I. Simon, Richard T. Lee

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Richard T. Lee, MD, Cardiovascular Division, Brigham and Women’s Hospital, 65 Landsdowne St, Cambridge, MA 02139. E-mail rlee{at}rics.bwh.harvard.edu

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)-B and abolished by overexpression of IB 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 p27^kip1, 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 (3x10⁹ pfu in 50 µL) 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.

Key Words: atherosclerosis • gene expression • growth factors • smooth muscle cells

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