Noiri E, Lee E, Testa J, Quigley J, Colflesh D, Keese C R, Giaever I, Goligorsky M S
Department of Medicine, State University of New York, Stony Brook 11794-8152, USA.
Am J Physiol. 1998 Jan;274(1):C236-44. doi: 10.1152/ajpcell.1998.274.1.C236.
Previously, we demonstrated the role of nitric oxide (NO) in transforming epithelial cells from a stationary to locomoting phenotype [E. Noiri, T. Peresleni, N. Srivastava, P. Weber, W.F. Bahou, N. Peunova, and M. S. Goligorsky. Am. J. Physiol. 270 (Cell Physiol. 39): C794-C802, 1996] and its permissive function in endothelin-1-stimulated endothelial cell migration (E. Noiri, Y. Hu, W. F. Bahou; C. Keese, I. Giaever, and M. S. Goligorsky, J. Biol: Chem. 272: 1747-1753, 1997). In the present study, the role of functional NO synthase in executing the vascular endothelial growth factor (VEGF)-guided program of endothelial cell migration and angiogenesis was studied in two independent experimental settings. First, VEGF, shown to stimulate NO release from simian virus 40-immortalized microvascular endothelial cells, induced endothelial cell transwell migration, whereas NG-nitro-L-arginine methyl ester (L-NAME) or antisense oligonucleotides to endothelial NO synthase suppressed this effect of VEGF. Second, in a series of experiments on endothelial cell wound healing, the rate of VEGF-stimulated cell migration was significantly blunted by the inhibition of NO synthesis. To gain insight into the possible mode of NO action, we next addressed the possibility that NO modulates cell matrix adhesion by performing impedance analysis of endothelial cell monolayers subjected to NO. The data showed the presence of spontaneous fluctuations of the resistance in ostensibly stationary endothelial cells. Spontaneous oscillations were induced by NO, which also inhibited cell matrix adhesion. This process we propose to term "podokinesis" to emphasize a scalar from of micromotion that, in the presence of guidance cues, e.g., VEGF, is transformed to a vectorial movement. In conclusion, execution of the program for directional endothelial cell migration requires two coexisting messages: NO-induced podokinesis (scalar motion) and guidance cues, e.g., VEGF, which imparts a vectorial component to the movement. Such a requirement for the dual signaling may explain a mismatch in the demand and supply with newly formed vessels in different pathological states accompanied by the inhibition of NO synthase.
此前，我们证明了一氧化氮（NO）在使上皮细胞从静止表型转变为运动表型中的作用[E. 诺伊里、T. 佩雷斯莱尼、N. 斯里瓦斯塔瓦、P. 韦伯、W.F. 巴胡、N. 佩诺娃和M.S. 戈利戈尔斯基。《美国生理学杂志》270（细胞生理学39）：C794 - C802，1996]及其在内皮素 - 1刺激的内皮细胞迁移中的促进作用（E. 诺伊里、Y. 胡、W.F. 巴胡；C. 基斯、I. 贾埃弗和M.S. 戈利戈尔斯基，《生物化学杂志》272：1747 - 1753，1997）。在本研究中，在两个独立的实验环境中研究了功能性NO合酶在执行血管内皮生长因子（VEGF）引导的内皮细胞迁移和血管生成程序中的作用。首先，已证明VEGF能刺激猿猴病毒40永生化微血管内皮细胞释放NO，它可诱导内皮细胞通过Transwell迁移，而NG - 硝基 - L - 精氨酸甲酯（L - NAME）或针对内皮型NO合酶的反义寡核苷酸可抑制VEGF的这种作用。其次，在一系列关于内皮细胞伤口愈合的实验中，抑制NO合成可显著减弱VEGF刺激的细胞迁移速率。为深入了解NO可能的作用方式，接下来我们通过对接受NO处理的内皮细胞单层进行阻抗分析，探讨了NO调节细胞与基质黏附的可能性。数据显示，表面静止的内皮细胞存在电阻的自发波动。NO可诱导自发振荡，同时它也抑制细胞与基质的黏附。我们建议将这个过程称为“足动”，以强调一种微观运动的标量形式，在存在引导信号（如VEGF）的情况下，它会转变为矢量运动。总之，内皮细胞定向迁移程序的执行需要两个并存的信号：NO诱导的足动（标量运动）和引导信号，如VEGF，它为运动赋予矢量成分。这种对双重信号传导的需求可能解释了在不同病理状态下伴随着NO合酶抑制时新形成血管的供需不匹配现象。
