Published online before print August 17, 2007, doi: 10.1161/CIRCRESAHA.107.151415
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Submitted on February 28, 2007
Revised on July 10, 2007
Accepted on August 3, 2007
Loss of the 
7 Integrin Promotes Extracellular Signal-Regulated Kinase Activation and Altered Vascular Remodeling
Jennifer V. Welser ;
From the Department of Pharmacology (J.V.W., N.L., C.A.S., M.E., P.S., W.T.G., D.J.B.), Nevada Transgenic Center (P.S., D.J.B.), and Department of Physiology (K.D.K.), University of Nevada School of Medicine, Reno.
* To whom correspondence should be addressed. E-mail: dburkin{at}medicine.nevada.edu.
Vascular smooth muscle cell (VSMC) proliferation and migration are underlying factors in the development and progression of cardiovascular disease. Studies have shown that altered expression of vascular integrins and extracellular matrix proteins may contribute to the vascular remodeling observed after arterial injury and during disease. We have recently shown that loss of the 
7
1 integrin results in VSMC hyperplasia. To investigate the cellular mechanisms underlying this phenotype, we have examined changes in cell signaling pathways associated with VSMC proliferation. Several studies have demonstrated the mitogen-activated protein kinase signaling pathway is activated in response to vascular injury and disease. In this study, we show that loss of the 7 integrin in VSMCs results in activation of the extracellular signal-regulated kinase and translocation of the activated kinase to the nucleus. Forced expression of the 7 integrin or use of the mitogen-activated protein kinase kinase 1 inhibitor U0126 in 7 integrin–deficient VSMCs suppressed extracellular signal-regulated kinase activation and restored the differentiated phenotype to 7 integrin–null cells in a manner dependent on Ras signaling. 7 Integrin–null mice displayed profound vascular remodeling in response to injury with pronounced neointimal formation and reduced vascular compliance. These findings demonstrate that the 71 integrin negatively regulates extracellular signal-regulated kinase activation and suggests an important role for this integrin as part of a signaling complex regulating VSMC phenotype switching.
Key words:
71 integrin •
ERK MAP kinase •
VSMC proliferation •
vascular remodeling •
integrin knockout mice
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