Dubey R K, Jackson E K, Lüscher T F
Department of Medicine and Research, University Hospitals Basel, Switzerland.
J Clin Invest. 1995 Jul;96(1):141-9. doi: 10.1172/JCI118014.
Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and AII on SMC migration; and (c) to evaluate the AII receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 microns pore size). AII stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhibited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5'-dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphorothioate (an inhibitor of the cAMP-dependent protein kinase). Low concentrations of the subtype AT1-receptor antagonist CGP 48933, but not the subtype AT2-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induced migration of vascular SMCs; (b) the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT1 receptor.
一氧化氮（NO）和血管紧张素II（AII）可影响血管平滑肌细胞（SMC）的增殖。然而，这些因子对SMC迁移（这一在血管病理生理学中同样重要的现象）的影响却很少受到关注。本研究的目的是：（a）确定NO是否抑制AII诱导的血管SMC迁移；（b）研究NO与AII在SMC迁移方面相互作用的机制；（c）评估介导AII诱导的SMC迁移的AII受体亚型。使用改良的Boyden小室（带有明胶包被的聚碳酸酯膜、孔径为8微米的Transwell小室）评估大鼠SMC的迁移。AII以浓度依赖性方式刺激SMC迁移，而硝普钠（SNP）和S-亚硝基-N-乙酰青霉胺（SNAP）可抑制这种作用。在L-精氨酸存在的情况下，而非D-精氨酸，诱导型NO合酶的诱导剂IL-1β也抑制AII诱导的SMC迁移，且这种作用可被NO合酶抑制剂N-硝基-L-精氨酸甲酯阻断。8-溴-cGMP可模拟NO供体对AII诱导的SMC迁移的作用。此外，LY83583（可溶性鸟苷酸环化酶抑制剂）和KT5823（cGMP依赖性蛋白激酶抑制剂）可部分抑制SNAP的抗迁移作用。虽然8-溴-cAMP（cAMP）也可模拟NO供体的抗迁移作用，但2'，5'-二脱氧腺苷（腺苷酸环化酶抑制剂）或（R）-p-腺苷-3'，5'-环硫代磷酸酯（cAMP依赖性蛋白激酶抑制剂）并不会改变SNAP的抗迁移作用。低浓度的AT1受体亚型拮抗剂CGP 48933可阻断AII诱导的SMC迁移，而AT2受体亚型拮抗剂CGP 42112则无此作用。这些发现表明：（a）NO抑制AII诱导的血管SMC迁移；（b）NO的抗迁移作用部分通过cGMP依赖性机制介导；（c）AII通过AT1受体刺激SMC迁移。
