Requirement of protein tyrosine phosphatase SHP2 for NO-stimulated vascular smooth muscle cell motility.
We have previously reported that nitric oxide (NO) increases the motility of differentiated cultured primary aortic smooth muscle cells from adult rats. There is little information on the role of protein tyrosine phosphatases in vascular biology. One such phosphatase, Src homology 2 phosphatase 2 (SHP2), is essential for motility. We tested the hypothesis that NO increases SHP2 levels via a cGMP-mediated mechanism and that this effect is necessary for NO-stimulated cell motility. Here we report that two different NO donors increased SHP2 protein levels and enzyme activity. This effect was mimicked by several cGMP agonists and blocked by an inhibitor of guanylyl cyclase. Specific decrease of SHP2 protein levels via the use of antisense oligodeoxynucleotides (ODNs), but not several control ODNs attenuated the motogenic effect of NO, which indicates the involvement of SHP2 in NO-elicited motogenesis. S-nitroso-N-acetylpenicillamine failed to increase SHP2 protein levels in subcultured aortic smooth muscle cells. This provides a potential explanation for the lack of effect of NO on cell motility in dedifferentiated subcultured cells. These results support the hypothesis that NO-elicited upregulation of SHP2 via a cGMP-mediated pathway is necessary for NO-induced motogenesis in differentiated aortic smooth muscle cells.
Brown
C
C
Department of Physiology and Vascular Biology Center, University of Tennessee, Memphis, Tennessee 38163-0001, USA.
Lin
Y
Y
Hassid
A
A
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D015854:Up-Regulation
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D020030:Nitric Oxide Donors; D016376:Oligonucleotides, Antisense; D010069:Oxadiazoles; D011810:Quinoxalines; D020098:Natriuretic Peptide, C-Type; C095048:microfilarial sheath protein, Helminth; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; D006152:Cyclic GMP