Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration
Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration
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DOI：
10.1161/hh1801.096338
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发表时间：
2001-09-14
影响因子：
20.1
通讯作者：
Hla, T
中科院分区：
文献类型：
--
作者：
Kluk, MJ;Hla, T
1-磷酸鞘氨醇（S1 P）是一种血小板衍生的G蛋白偶联受体（GPCR）EDG-1家族的配体，最近已成为血管发育的调节剂。尽管S1 P对内皮细胞和血管平滑肌细胞（VSMCs）具有有效的作用，但后一种细胞类型中特异性S1 P受体的功能尚不清楚。在这里，我们表明，小狗内膜VSMCs表达更高水平的EDG-1 mRNA比成人内侧VSMCs。EDG-1稳定转染入成人内侧VSMCs增强了其对S1 P的增殖反应，同时诱导了p70 S6激酶活性和细胞周期蛋白D1的表达。百日咳毒素处理抑制S1 P诱导的p70 S6激酶激活、细胞周期蛋白D1表达和增殖，表明EDG-1与GI途径的偶联至关重要。此外，用雷帕霉素阻断p70 S6激酶磷酸化可抑制细胞周期蛋白D1的表达和增殖，表明p70 S6激酶的激活在EDG-1/G（i）介导的细胞增殖中至关重要。EDG-1的表达也显著增强了成人内侧VSMCs对S1 P的迁移反应。S1 P诱导的表达外源性EDG-1的成人内侧VSMCs迁移需要Gi激活，但不需要p70 S6激酶。这些结果表明，EDG-1在VSMCs中的表达增强显著刺激对S1 P的增殖和迁移反应。由于EDG-1在VSMCs的pup-intimal表型中表达，因此通过EDG-1的S1 P信号传导可能在VSMCs增殖和迁移失调的血管疾病中发挥作用。
Sphingosine 1-phosphate (S1P), a platelet-derived ligand for the EDG-1 family of G protein-coupled receptors (GPCRs), has recently emerged as a regulator of vascular development. Although S1P has potent effects on endothelial cells and vascular smooth muscle cells (VSMCs), the functions of the specific S1P receptors in the latter cell type are not known. Here we show that pup-intimal VSMCs express higher levels of EDG-1 mRNA than adult-medial VSMCs. Stable transfection of EDG-1 into adult-medial VSMCs enhanced their proliferative response to S1P, concomitant with induction of p70 S6 kinase activity and expression of cyclin D1. Pertussis toxin treatment inhibited S1P-induced p70 S6 kinase activation, cyclin D1 expression and proliferation, suggesting that EDG-1-coupling to the Gi pathway is critical. Furthermore, blocking p70 S6 kinase phosphorylation with rapamycin inhibited cyclin D1 expression and proliferation, suggesting that activation of p70 S6 kinase is critical in EDG-1/G(i)-mediated cell proliferation. EDG-1 expression also profoundly enhanced the migratory response of adult-medial VSMCs to S1P. S1P-induced migration of adult-medial VSMCs expressing exogenous EDG-1 required Gi activation but not p70 S6 kinase. These results suggest that enhanced expression of EDG-1 in VSMCs dramatically stimulates both the proliferative and migratory responses to S1P. Since EDG-1 is expressed in the pup-intimal phenotype of VSMCs, S1P signaling via EDG-1 may play a role in vascular diseases in which the proliferation and migration of VSMCs are dysregulated.