Kidney Research Centre, University of Ottawa/Ottawa Hospital Research Institute, 451 Smyth Rd, Ottawa, Ontario KIH 8M5, Canada.
Hypertension. 2011 Apr;57(4):809-18. doi: 10.1161/HYPERTENSIONAHA.110.162719. Epub 2011 Mar 7.
Sphingosine-1-phosphate (S1P), a multifunctional phospholipid, regulates vascular cell function. Whether S1P influences vascular inflammatory responses, particularly in hypertension, is unclear. We tested the hypothesis that S1P is a proinflammatory mediator signaling through receptor tyrosine kinase transactivation and that responses are amplified in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSPs), a model in which we demonstrated Edg1 (S1P1 receptor) to be a candidate gene for salt-sensitive hypertension. Vascular smooth muscle cell from Wistar-Kyoto rats and SHRSPs were studied. S1P receptor subtypes, S1P1 and S1P2, were similarly expressed in Wistar-Kyoto rats and SHRSPs. S1P induced phosphorylation of epidermal growth factor receptor and platelet-derived growth factor and activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, with amplified effects in SHRSPs versus Wistar-Kyoto rats. Inhibition of epidermal growth factor receptor and platelet-derived growth factor (with AG1478 and AG1296, respectively) abolished S1P-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase in Wistar-Kyoto rats with variable effects in SHRSPs. Vascular smooth muscle cell inflammation was evaluated by expression of adhesion molecules and functional responses assessed by monocyte adhesion. S1P stimulated expression of intercellular adhesion molecule 1 and vascular cell adhesion protein 1 and promoted monocyte adhesion, particularly in SHRSP cells. S1P-mediated inflammation was blunted by AG1478 and AG1296 in SHRSP cells. VPC23019, a S1P1 receptor antagonist, inhibited S1P-induced mitogen-activated protein kinase phosphorylation, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression, and monocyte adhesion. Our data indicate that molecular processes underlying vascular inflammation and cell adhesion in SHRSPs involve S1P/S1P1 receptors and phosphorylation of receptor tyrosine kinases. We identify a novel pathway linking S1P/S1P1 receptors to specific proinflammatory signaling pathways through epidermal growth factor receptor and platelet-derived growth factor transactivation, a process that is upregulated in SHRSPs. Such molecular events may contribute to vascular inflammation in hypertension.
鞘氨醇-1-磷酸（S1P）是一种多功能磷脂，可调节血管细胞功能。S1P 是否影响血管炎症反应，特别是在高血压中，尚不清楚。我们检验了这样一个假设，即 S1P 通过受体酪氨酸激酶的转激活作用成为一种促炎介质信号，并且这种反应在易发生中风的自发性高血压大鼠（SHRSP）的血管平滑肌细胞中被放大，我们在该模型中证明 Edg1（S1P1 受体）是盐敏感性高血压的候选基因。研究了 Wistar-Kyoto 大鼠和 SHRSP 的血管平滑肌细胞。Wistar-Kyoto 大鼠和 SHRSP 中的 S1P 受体亚型 S1P1 和 S1P2 表达相似。S1P 诱导表皮生长因子受体和血小板衍生生长因子的磷酸化，并激活 p38 丝裂原活化蛋白激酶和 c-Jun N-末端激酶，而 SHRSP 中的作用比 Wistar-Kyoto 大鼠更强。用 AG1478 和 AG1296（分别为表皮生长因子受体和血小板衍生生长因子抑制剂）抑制 S1P 诱导的 Wistar-Kyoto 大鼠 p38 丝裂原活化蛋白激酶和 c-Jun N-末端激酶磷酸化，对 SHRSP 的作用则不同。通过表达粘附分子和通过单核细胞粘附评估功能反应来评估血管平滑肌细胞炎症。S1P 刺激细胞间粘附分子 1 和血管细胞粘附蛋白 1 的表达，并促进单核细胞粘附，尤其是在 SHRSP 细胞中。AG1478 和 AG1296 可减轻 SHRSP 细胞中 S1P 介导的炎症。S1P1 受体拮抗剂 VPC23019 抑制 S1P 诱导的丝裂原活化蛋白激酶磷酸化、细胞间粘附分子 1 和血管细胞粘附蛋白 1 的表达以及单核细胞粘附。我们的数据表明，SHRSP 中血管炎症和细胞粘附的分子过程涉及 S1P/S1P1 受体和受体酪氨酸激酶的磷酸化。我们确定了一种新的途径，通过表皮生长因子受体和血小板衍生生长因子的转激活作用将 S1P/S1P1 受体与特定的促炎信号通路连接起来，该过程在 SHRSP 中被上调。这种分子事件可能导致高血压中的血管炎症。
