Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033524.92083.64
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Submitted on April 17, 2002
Revised on July 23, 2002
Accepted on July 31, 2002
Nitric Oxide
Induced Motility in Aortic Smooth Muscle Cells. Role of Protein Tyrosine Phosphatase SHP-2 and GTP-Binding Protein Rho
Yingzi Chang ;
From the Department of Physiology and Vascular Biology Center, University of Tennessee, Memphis.
* To whom correspondence should be addressed. E-mail: ahassid{at}physio1.utmem.edu.
We have previously reported that SHP-2 upregulation is necessary for NO-stimulated motility in differentiated rat aortic smooth muscle cells. We now test the hypothesis that upregulation of SHP-2 is necessary and sufficient to stimulate cell motility. Overexpression of SHP-2 via recombinant adenoviral vector stimulated motility to the same extent as NO, whereas the expression of C463S-SHP-2, the dominant-negative SHP-2 allele, blocked the motogenic effect of NO. On the basis of previous studies, we next tested the hypothesis that NO decreases RhoA activity and that this event is necessary and sufficient to explain NO-induced motogenesis. We found that NO decreased RhoA activity in a concentration-dependent manner. Moreover, a dominant-negative SHP-2 allele, DSH2, blocked the NO-induced inhibition of RhoA activity, indicating that upregulation of SHP-2 is necessary for this event. Expression of G14V-RhoA, the constitutively active RhoA allele, decreased cell motility and blocked the motogenic effect of NO, whereas the expression of T19N-RhoA, the dominant-negative RhoA allele, increased cell motility to an extent similar to that induced by NO. Dominant-negative RhoA reversed the effect of dominant-negative SHP-2, indicating that RhoA functions downstream from SHP-2. To investigate events downstream from RhoA, we treated cells with fasudil, a selective Rho kinase inhibitor, and found that it increased cell motility. These results indicate that upregulation of SHP-2, leading to downregulation of RhoA, which is followed by decreased Rho kinase activity, is a sequence of events necessary and sufficient to explain NO-induced cell motility in differentiated aortic smooth muscle cells. The results may be of relevance to in vivo events such as neointimal formation, angiogenesis, and vasculogenesis.
Key words: nitric oxide • SHP-2 • Rho • cell motility
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