Kim Kwan-Sik, Ren Juan, Jiang Ying, Ebrahem Quteba, Tipps Russell, Cristina Kelly, Xiao Yi-jin, Qiao Jing, Taylor Kevin L, Lum Hazel, Anand-Apte Bela, Xu Yan
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
FASEB J. 2005 May;19(7):819-21. doi: 10.1096/fj.04-2988fje. Epub 2005 Feb 17.
Angiogenesis is critical for many physiological and pathological processes. We show here that the lipid sphingosylphosphorylcholine (SPC) induces angiogenesis in vivo and GPR4 is required for the biological effects of SPC on endothelial cells (EC). In human umbilical vein EC, down-regulation of GPR4 specifically inhibits SPC-, but not sphingosine-1-phosphate-, or vascular endothelial growth factor (VEGF)-induced tube formation. Re-introduction of GPR4 fully restores the activity of SPC. In microvascular EC, GPR4 plays a pivotal role in cell survival, growth, migration, and tube formation through both SPC-dependent and -independent pathways. The biological effects resulting from SPC/GPR4 interactions involve the activation of both phosphatidylinositol-3 kinase and Akt. Moreover, the effects of SPC on EC require SPC induced trans-phosphorylation and activation of the VEGF receptor 2. These results identify SPC and its receptor, GPR4, as critical regulators of the angiogenic potential of EC.
血管生成对许多生理和病理过程至关重要。我们在此表明，脂质鞘氨醇磷酸胆碱（SPC）在体内诱导血管生成，并且GPR4是SPC对内皮细胞（EC）产生生物学效应所必需的。在人脐静脉内皮细胞中，GPR4的下调特异性抑制SPC诱导的，而非1-磷酸鞘氨醇或血管内皮生长因子（VEGF）诱导的管腔形成。重新引入GPR4可完全恢复SPC的活性。在微血管内皮细胞中，GPR4通过SPC依赖和非依赖途径在细胞存活、生长、迁移和管腔形成中起关键作用。SPC / GPR4相互作用产生的生物学效应涉及磷脂酰肌醇-3激酶和Akt的激活。此外，SPC对内皮细胞的作用需要SPC诱导的VEGF受体2的反式磷酸化和激活。这些结果确定SPC及其受体GPR4是内皮细胞血管生成潜能的关键调节因子。
