Brown C, Pan X, Hassid A
Department of Physiology and Biophysics, University of Tennessee, 894 Union Ave, Memphis, Tenn.38163-0001, USA.
Circ Res. 1999 Apr 2;84(6):655-67. doi: 10.1161/01.res.84.6.655.
Migration of aortic smooth muscle cells is thought to be of essential importance in vascular restenosis, remodeling, and angiogenesis. Recent studies have shown that NO donors inhibit the migration of subcultured aortic smooth muscle cells. However, there is evidence that NO elicits opposite effects on cell proliferation in primary versus subcultured cells, indicating fundamental differences among different models of aortic smooth muscle cell cultures. The purpose of the current study was to investigate the effect of NO donors on migration of primary cultures of rat aortic smooth muscle cells and to compare and contrast their response with those in subcultured cells. A second purpose was to investigate some of the underlying mechanisms associated with NO-induced effects on cell migration. We report that 2 NO donors, S-nitroso-N-acetylpenicillamine (SNAP) and 2, 2-(hydroxynitrosohydrazino)bis-ethanamine, stimulated the migration of primary cells in a wounded-culture model as well as in a transwell migration model. The effect of NO donors was mimicked by 2 cGMP analogues and C-type natriuretic peptide and blocked by a specific inhibitor of guanyl cyclase, 1H-(1,2,4)oxadiazolo[4,3, -a]quinoxalin-1-one, indicating the involvement of cGMP as second messenger. Moreover, neither NO donors nor cGMP analogues altered migration of primary cultures stimulated by either FBS or angiotensin II. In contrast to its effect in primary cultures, SNAP did not alter basal or stimulated migration of subcultured cells, except at a relatively high concentration of 1 mmol/L, at which migration was inhibited. The migration-stimulatory effect of NO donors and cGMP was associated with altered cell morphology and dissociation of actin filaments, consistent with recent studies indicating that cell morphology and cytoskeletal organization influence cell migration. The results suggest the possible involvement of NO-induced cell migration in vascular injury or remodeling, representing conditions in which vascular NO levels would be expected to be elevated.
主动脉平滑肌细胞的迁移被认为在血管再狭窄、重塑和血管生成中至关重要。最近的研究表明，一氧化氮供体可抑制传代培养的主动脉平滑肌细胞的迁移。然而，有证据表明，一氧化氮对原代细胞与传代培养细胞的增殖产生相反的影响，这表明不同模型的主动脉平滑肌细胞培养存在根本差异。本研究的目的是研究一氧化氮供体对大鼠主动脉平滑肌细胞原代培养物迁移的影响，并将其反应与传代培养细胞的反应进行比较和对比。第二个目的是研究与一氧化氮诱导的细胞迁移效应相关的一些潜在机制。我们报告，两种一氧化氮供体，S-亚硝基-N-乙酰青霉胺（SNAP）和2,2-（羟基亚硝基肼基）双乙胺，在创伤培养模型以及Transwell迁移模型中刺激了原代细胞的迁移。两种环鸟苷酸类似物和C型利钠肽模拟了一氧化氮供体的作用，并被鸟苷酸环化酶的特异性抑制剂1H-（1,2,4）恶二唑并[4,3,-a]喹喔啉-1-酮阻断，表明环鸟苷酸作为第二信使参与其中。此外，一氧化氮供体和环鸟苷酸类似物均未改变由胎牛血清或血管紧张素II刺激的原代培养物的迁移。与它在原代培养中的作用相反，SNAP除了在相对较高的1 mmol/L浓度下抑制迁移外，并未改变传代培养细胞的基础迁移或刺激迁移。一氧化氮供体和环鸟苷酸的迁移刺激作用与细胞形态改变和肌动蛋白丝解离有关，这与最近表明细胞形态和细胞骨架组织影响细胞迁移的研究一致。结果表明，一氧化氮诱导的细胞迁移可能参与血管损伤或重塑，这代表了血管一氧化氮水平预计会升高的情况。
