Published online before print February 10, 2005, doi: 10.1161/01.RES.0000159182.98874.43
© 2005 American Heart Association, Inc.
Cellular Biology |
Cyclic Strain Inhibits Notch Receptor Signaling in Vascular Smooth Muscle Cells In Vitro
From the Vascular Health Research Centre (D.M., C.S., Y.A.B., P.M.C., P.A.C.), Faculty of Science and Health, and the School of Biotechnology and the National Centre for Sensor Research (D.W.), Dublin City University, Ireland; and Department of Surgery (E.M.R.), University of Rochester Medical Center, Rochester, NY.
Correspondence to Dr Yvonne Birney, Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland. E-mail yvonne.birney{at}dcu.ie
Notch signaling has been shown recently to regulate vascular cell fate in adult cells. By applying a uniform equibiaxial cyclic strain to vascular smooth muscle cells (SMCs), we investigated the role of strain in modulating Notch-mediated growth of SMCs in vitro. Rat SMCs cultured under conditions of defined equibiaxial cyclic strain (0% to 15% stretch; 60 cycles/min; 0 to 24 hours) exhibited a significant temporal and force-dependent reduction in Notch 3 receptor expression, concomitant with a significant reduction in Epstein Barr virus latency C promoter-binding factor-1/recombination signal-binding protein of the J
immunoglobulin gene–dependent Notch target gene promoter activity and mRNA levels when compared with unstrained controls. The decrease in Notch signaling was Gi-protein– and mitogen-activated protein kinase–dependent. In parallel cultures, cyclic strain inhibited SMC proliferation (cell number and proliferating cell nuclear antigen expression) while significantly promoting SMC apoptosis (annexin V binding, caspase-3 activity and bax/bcl-xL ratio). Notch 3 receptor overexpression significantly reversed the strain-induced changes in SMC proliferation and apoptosis to levels comparable to unstrained control cells, whereas Notch inhibition further potentiated the changes in SMC apoptosis and proliferation. These findings suggest that cyclic strain inhibits SMC growth while enhancing SMC apoptosis, in part, through regulation of Notch receptor and downstream target gene expression.
Key Words: notch • cyclic strain • apoptosis • proliferation • vascular • G-proteins
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