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1 Department of Physiology and Vascular Biology, University of Tennessee, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: ahassid{at}physio1.utmem.edu.
Vascular injury increases NO levels and this effect may play a counter regulatory role in neointima formation, by decreasing vascular smooth muscle cell motility. However, the mechanisms underlying this effect are not well established. We tested the hypothesis that NO decreases cell motility by increasing the activity of a protein tyrosine phosphatase, PTP-PEST, in cultured rat aortic smooth muscle cells. Two NO donors increased the activity of PTP-PEST. A cGMP analogue mimicked the effect of NO whereas a guanyl cyclase inhibitor blocked it, indicating that elevated cGMP is both necessary and sufficient to induce PTP-PEST activity. Overexpression of wild type PTP-PEST induced antimotogenesis whereas expression of dominant negative-PTP-PEST blocked the antimotogenic effect of NO, indicating that increased PTP-PEST activity is both sufficient and necessary to explain the effect of NO. Overexpression of PTP-PEST mimicked NO-induced dephosphorylation of adapter protein p130cas whereas dominant negative-PTP-PEST blocked the effect of NO, indicating that upregulation of PTP-PEST is both necessary and sufficient to explain NO-induced p130cas dephosphorylation. Expression of a substrate domain deleted p130cas decreased motogenesis whereas overexpression of wild type p130cas blocked the antimotogenic effect of NO, indicating the functional importance of p130Cas dephosphorylation. NO induced dissociation of the Cas-Crk complex, an effect that was mimicked by overexpression of PTP-PEST and opposed by expression of dominant negative PTP-PEST. Our results indicate that NO decreases aortic smooth muscle cell motility via a cGMP-mediated mechanism, involving upregulation of PTP-PEST, in turn inducing dephosphorylation of p130cas, and likely involving Cas-Crk dissociation as a downstream event.
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