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1 Bioengineering, Pennsylvania State University, University Park, PA, USA
2 Biomedical Engineering, City College of New York/CUNY, New York, NY, USA
* To whom correspondence should be addressed. E-mail: tarbell{at}ccny.cuny.edu.
Vascular smooth muscle cell (SMC) migration and proliferation are hallmarks of intimal hyperplasia (IH). Previous studies have shown that IH progression is affected by hemodynamic conditions at the diseased site. These observations, coupled with the realization that SMCs are exposed to blood flow in both denuded vessels (direct contact with the flowing blood) and intact vessels (interstitial blood flow driven by the transmural pressure gradient), motivate this study of the effects of fluid flow shear stress (SS) on SMC migration. While several in vitro studies have elucidated the effects of SS on SMC proliferation, the influence of SS on SMC migration has not yet been determined. We therefore grew rat aortic SMCs on Matrigel-coated cell culture inserts and quantified their migratory activity toward platelet-derived growth factor (PDGF)-BB when exposed to 1, 10, or 20 dyn/cm2 SS in a rotating disk apparatus for 1-4 hours. 4 hours of either 10 or 20 dyn/cm2 SS significantly inhibited SMC migration through the Matrigel layer to the bottom side of the insert. This inhibition was associated with downregulation of SMC matrix metalloproteinase (MMP)-2 activation in response to SS. 4 hours of 10 dyn/cm2 SS also drastically increased the production of nitric oxide (NO) by SMCs. Addition of a NO synthase inhibitor (NG-nitro-L-arginine methyl ester; 100 µM) to cells abolished the shear-induced increase in NO production as well as the inhibition of SMC migration and MMP-2 activity. Through the use of a NO donor (S-nitroso-N-acetylpenicillamine; 500 µM), it was shown that NO acts to suppress SMC migration via the reduction of both total (proenzyme + active) and active MMP-2 levels. Addition of 10 µM MMP-2 inhibitor (MMP-2 Inhibitor I) to inserts significantly reduced SMC migration. Western blots showed no effect of 4 hours of 20 dyn/cm2 SS on SMC production of PDGF-AA, another chemical known to suppress SMC migration. Thus, it appears that SS acts to suppress SMC migration by upregulating the cellular production of NO which in turn inhibits MMP-2 activity.
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