Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells

Abstract

Pu Q, Zhuang D, Thakran S, Hassid A. Mechanisms related to NO-induced motility in differentiated rat aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 300: H101-H108, 2011. First published October 29, 2010 doi:10.1152/ajpheart.00342.2010 is thought to play an important role as an inhibitor of vascular cell proliferation, motility, and neointima formation. This effect is mediated, in part, via the upregulation of protein tyrosine phosphatase (PTP)1B. Conversely, studies have reported that in presumably hyperinsulinemic mice fed a high-fat diet, NO enhances vascular remodeling, whereas a deficit of NO attenuates vascular remodeling. We have reported that in differentiated cultured smooth muscle cells treated with insulin, NO induces a motogenic effect that is dependent on Src homology-2 domain PTP 2 (SHP2) upregulation. In the present study, we describe novel mechanisms relevant to the motogenic effect of NO. Treatment of cultured cells with the selective angiontensin type 1 receptor antagonist losartan, but not with the selective angiotensin type 2 receptor antagonist PD-123319, blocked the comotogenic capacity of NO and insulin. Insulin and NO increased the secretion of ANG II into the culture media by 2-and 2.5-fold (P Ͻ 0.05), respectively, whereas treatment of cells with ANG II uncovered the motogenic effect of NO (1.4-fold above control, P Ͻ 0.05) and decreased the levels of PTP1B to 45% of control (P Ͻ 0.05). Suppression of PTP1B function was sufficient to uncover the motogenic effect of NO. The capacity of insulin to suppress PTP1B activity was blocked by losartan, implicating ANG II function in mediating this effect. Both insulin and ANG II induced the upregulation of phosphatidyl inositol 3-kinase (PI3K)-␦ by two-to threefold (P Ͻ 0.05), and this effect was both necessary and sufficient to uncover NO-induced motogenesis. Finally, suppression of PTP1B function potentiated, whereas overexpression of PTP1B inhibited, SHP2-induced motogenesis. These results support the hypothesis that the comotogenic effect of insulin and NO occurs via an ANG II-mediated effect involving the suppression of PTP1B and upregulation of PI3K-␦ and SHP2. nitric oxide; vascular smooth muscle; angiotensin II; protein tyrosine phosphatases NITRIC OXIDE (NO) is generally thought to attenuate vascular remodeling, and numerous studies have reported that it decreases neointima formation and atherosclerosis in models of vascular injury. In vivo, inducible NO synthase (iNOS) levels have been reported to be increased in medial cells, almost immediately after vascular injury, and subsequently in neointimal cells (12,34). Inducible NO levels are also increased in diabetes. Several groups, including ours, have reported that NO donors decrease aortic smooth muscle cell motility and proliferation in culture (11,24,26). Moreover, many in vivo studies have shown that exogenous or endogenous NO attenuates neointima formation induced by vascular injury, consistent with the overall inhibition of vascular smooth muscle cell motility and pro...

Protein tyrosine phosphatase PTP1B in cell adhesion and migration

“…PTP1B was shown to promote cell adhesion and motility in fibroblasts, 17,18 neurons, 3,19 platelets, 4 and several tumor cell lines. 12,[20][21][22] An inhibitory role has been described in fibroblasts, 23,24 primary aortic smooth muscle cells, 25 ovarian cancer cells, 26 and in glioblastoma multiforme tumor cell invasion in mice. 27 Remarkably, the positive role of PTP1B in cell motility was frequently associated with the stimulation of integrin-dependent signaling.…”

“…3,4,12,17,18,22 In contrast, the negative effect of PTP1B on cell motility was related to antagonizing signaling from growth factor receptor tyrosine kinases. [24][25][26][27] In a recent quantitative study, we analyzed the intrinsic motility and migration parameters of PTP1B-null cells (KO cells) in an isotropic 2-D fibronectin substratum. 28 Directionality and average velocity of KO cells were significantly reduced when compared with KO cells reconstituted with wild-type PTP1B (WT cells).…”

Topological control of nitric oxide secretion by tantalum oxide nanodot arrays

“…The cardiovascular diseases are mainly related with the eNOS and iNOS. It has previously been shown that the lipopolysaccharides and the cytokines regulate the iNOS present in the cells at the transcriptional level [ 31 ]. Some recent studies have also shown that in the iNOS pathway, NF-kB controls the iNOS expression which in-turn is targeted by Akt/ILK/TNF-α [ 32 ].…”