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(Circulation Research. 2007;101:e44.)
© 2007 American Heart Association, Inc.

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Cadherins, RhoA, and Rac1 Are Differentially Required for Stretch-Mediated Proliferation in Endothelial Versus Smooth Muscle Cells

Wendy F. Liu, Celeste M. Nelson, John L. Tan, Christopher S. Chen

From the Department of Biomedical Engineering (W.F.L., C.M.N., J.L.T.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Bioengineering (W.F.L., C.S.C.), University of Pennsylvania, Philadelphia.

Correspondence to Christopher S. Chen, Skirkanich Hall, Suite 510, 210 South 33rd St, Philadelphia, PA 19104. E-mail chrischen{at}seas.upenn.edu

Abnormal mechanical forces can trigger aberrant proliferation of endothelial and smooth muscle cells, as observed in the progression of vascular diseases such as atherosclerosis. It has been previously shown that cells can sense physical forces such as stretch through adhesions to the extracellular matrix. Here, we set out to examine whether cell–cell adhesions are also involved in transducing mechanical stretch into a proliferative response. We found that both endothelial and smooth muscle cells exhibited an increase in proliferation in response to stretch. Using micropatterning to isolate the role of cell–cell adhesion from cell–extracellular matrix adhesion, we demonstrate that endothelial cells required cell–cell contact and vascular endothelial cadherin engagement to transduce stretch into proliferative signals. In contrast, smooth muscle cells responded to stretch without contact to neighboring cells. We further show that stretch stimulated Rac1 activity in endothelial cells, whereas RhoA was activated by stretch in smooth muscle cells. Blocking Rac1 signaling by pharmacological or adenoviral reagents abrogated the proliferative response to stretch in endothelial cells but not in smooth muscle cells. Conversely, blocking RhoA completely inhibited the proliferative response in smooth muscle cells but not in endothelial cells. Together, these data suggest that vascular endothelial cadherin has an important role in mechanotransduction and that endothelial and smooth muscle cells use different mechanisms to respond to stretch.

Key Words: atherosclerosis • cadherin • cell cycle progression • mechanical stretch • mechanotransduction • Rho