Published online before print October 30, 2003, doi: 10.1161/01.RES.0000103635.38096.2F
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Submitted on December 23, 2002
Revised on October 15, 2003
Accepted on October 16, 2003
Biomechanically Induced Gene iex-1 Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
P. Christian Schulze ;
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. 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 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 (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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