Kevil Christopher G, Orr A Wayne, Langston Will, Mickett Kathryn, Murphy-Ullrich Joanne, Patel Rakesh P, Kucik Dennis F, Bullard Daniel C
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
J Biol Chem. 2004 Apr 30;279(18):19230-8. doi: 10.1074/jbc.M312025200. Epub 2004 Feb 24.
Coordinated regulation of endothelial cell migration is an integral process during angiogenesis. However, molecular mechanisms regulating endothelial cell migration remain largely unknown. Increased expression of cell adhesion molecules has been implicated during angiogenesis, yet the precise role of these molecules is unclear. Here, we examined the hypothesis that intercellular adhesion molecule-1 (ICAM-1) is important for endothelial cell migration. Total cell displacement and directional migration were significantly attenuated in ICAM-1-deficient endothelium. Closer examination of ICAM-1-deficient cells revealed decreased Akt Thr(308) and endothelial nitric-oxide synthase Ser(1177) phosphorylation and NO bioavailability, increased actin stress fiber formation, and a lack of distinct cell polarity compared with wild-type endothelium. Supplementation of ICAM-1 mutant cells with the NO donor DETA NONOate (0.1 microM) corrected the migration defect, diminished stress fiber formation, and enhanced pseudopod and uropod formation. These data demonstrate that ICAM-1 facilitates the development of cell polarity and modulates endothelial cell migration through a pathway regulating endothelial nitric-oxide synthase activation and organization of the actin cytoskeleton.
内皮细胞迁移的协调调节是血管生成过程中的一个不可或缺的环节。然而，调节内皮细胞迁移的分子机制仍 largely 未知。细胞粘附分子表达的增加在血管生成过程中已有牵连，但这些分子的确切作用尚不清楚。在此，我们检验了细胞间粘附分子-1（ICAM-1）对内皮细胞迁移很重要这一假说。在 ICAM-1 缺陷的内皮细胞中，总细胞位移和定向迁移显著减弱。与野生型内皮细胞相比，对 ICAM-1 缺陷细胞的进一步检查发现 Akt Thr(308) 和内皮型一氧化氮合酶 Ser(1177) 的磷酸化以及 NO 生物利用度降低，肌动蛋白应力纤维形成增加，且缺乏明显的细胞极性。用 NO 供体 DETA NONOate（0.1 microM）补充 ICAM-1 突变细胞可纠正迁移缺陷，减少应力纤维形成，并增强伪足和尾足形成。这些数据表明，ICAM-1 通过调节内皮型一氧化氮合酶激活和肌动蛋白细胞骨架组织的途径促进细胞极性的发展并调节内皮细胞迁移。
