English D, Welch Z, Kovala A T, Harvey K, Volpert O V, Brindley D N, Garcia J G
Experimental Cell Research Program, Methodist Research Institute, Indianapolis, Indiana 46202, USA.
FASEB J. 2000 Nov;14(14):2255-65. doi: 10.1096/fj.00-0134com.
Recent studies have identified factors responsible for angiogenesis within developing tumors, but mediators of vessel formation at sites of trauma, injury, and wound healing are not clearly established. Here we show that sphingosine 1-phosphate (S1P) released by platelets during blood clotting is a potent, specific, and selective endothelial cell chemoattractant that accounts for most of the strong endothelial cell chemotactic activity of blood serum, an activity that is markedly diminished in plasma. Preincubation of endothelial cells with pertussis toxin inhibited this effect of S1P, demonstrating the involvement of a Galphai-coupled receptor. After S1P-induced migration, endothelial cells proliferated avidly and differentiated forming multicellular structures suggestive of early blood vessel formation. S1P was strikingly effective in enhancing the ability of fibroblast growth factor to induce angiogenesis in the avascular mouse cornea. Our results show that blood coagulation initiates endothelial cell angiogenic responses through the release of S1P, a potent endothelial cell chemoattractant that exerts its effects by activating a receptor-dependent process.
近期研究已确定了发育中肿瘤内血管生成的相关因素，但对于创伤、损伤及伤口愈合部位血管形成的介质尚未明确。在此，我们发现血小板在血液凝固过程中释放的1-磷酸鞘氨醇（S1P）是一种强效、特异且具有选择性的内皮细胞趋化因子，它构成了血清中大部分强大的内皮细胞趋化活性，而这种活性在血浆中显著降低。用百日咳毒素对内皮细胞进行预孵育可抑制S1P的这种作用，表明其涉及一种Gαi偶联受体。在S1P诱导迁移后，内皮细胞大量增殖并分化形成提示早期血管形成的多细胞结构。S1P在增强成纤维细胞生长因子诱导无血管小鼠角膜血管生成的能力方面极为有效。我们的结果表明，血液凝固通过释放S1P启动内皮细胞血管生成反应，S1P是一种强效的内皮细胞趋化因子，通过激活受体依赖性过程发挥作用。
