Aims The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis. It is controversial whether this happens by filtration or regulated transendothelial transport. Because sphingosine-1-phosphate (S1P) preserves the endothelial barrier, we investigated in vivo and in vitro, whether S1P and its cognate S1P receptor 3 (S1P3) regulate the transendothelial transport of lipoproteins. Methods and Results Compared to apoE-haploinsufficient mice (CTRL), apoE-haploinsufficient mice with additional endothelium specific knock-in of S1P3 (S1P3-iECKI) showed decreased transport of LDL and Evan’s Blue but increased transport of HDL from blood into the peritoneal cave. After 30 weeks of high-fat diet feeding, S1P3-iECKI mice had lower levels of non-HDL-cholesterol and less atherosclerosis than CTRL mice. In vitro, stimulation with an S1P3 agonist increased the transport of 125I-HDL but decreased the transport of 125I-LDL through human aortic endothelial cells (HAECs). Conversely, inhibition or knock-down of S1P3 decreased the transport of 125I-HDL but increased the transport of 125I-LDL. Silencing of SCARB1 encoding scavenger receptor B1 (SR-BI) abrogated the stimulation of 125I-HDL transport by the S1P3 agonist. The transendothelial transport of 125I-LDL was decreased by silencing of SCARB1 or ACVLR1 encoding activin-like kinase 1 but not by interference with LDLR. None of the three knock-downs prevented the stimulatory effect of S1P3 inhibition on transendothelial 125I-LDL transport. Conclusion S1P3 regulates the transendothelial transport of HDL and LDL oppositely by SR-BI-dependent and SR-BI-independent mechanisms, respectively. This divergence supports a contention that lipoproteins pass the endothelial barrier by specifically regulated mechanisms rather than passive filtration.

中文翻译：

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1-磷酸鞘氨醇受体 3 以相反的方式调节 HDL 和 LDL 的跨内皮转运

目的 脂蛋白从血液进入动脉壁是动脉粥样硬化的限速步骤。这是通过过滤还是通过调节的跨内皮运输发生的，目前存在争议。由于 1-磷酸鞘氨醇 (S1P) 可以保护内皮屏障，因此我们在体内和体外研究了 S1P 及其同源 S1P 受体 3 (S1P3) 是否调节脂蛋白的跨内皮转运。方法和结果与 apoE 单倍体不足小鼠 (CTRL) 相比，额外内皮特异性敲入 S1P3 (S1P3-iECKI) 的 apoE 单倍体不足小鼠显示 LDL 和伊文蓝转运减少，但 HDL 从血液转运至腹膜腔的转运增加。经过 30 周的高脂肪饮食喂养后，S1P3-iECKI 小鼠的非 HDL 胆固醇水平低于 CTRL 小鼠，动脉粥样硬化也较少。在体外，S1P3 激动剂的刺激增加了 125I-HDL 的转运，但减少了 125I-LDL 通过人主动脉内皮细胞 (HAEC) 的转运。相反，抑制或敲低S1P3会减少125I-HDL的转运，但会增加125I-LDL的转运。编码清道夫受体 B1 (SR-BI) 的 SCARB1 沉默消除了 S1P3 激动剂对 125I-HDL 转运的刺激。沉默编码激活素样激酶 1 的 SCARB1 或 ACVLR1 可减少 125I-LDL 的跨内皮转运，但不会通过干扰 LDLR 来减少。三种敲低均未阻止 S1P3 抑制对跨内皮 125I-LDL 转运的刺激作用。结论 S1P3分别通过SR-BI依赖性和SR-BI非依赖性机制反向调节HDL和LDL的跨内皮转运。这种分歧支持脂蛋白通过特定调节机制而不是被动过滤穿过内皮屏障的论点。