Endothelial Spns2 and ApoM Regulation of Vascular Tone and Hypertension Via Sphingosine-1-Phosphate.
Endothelial Spns2 and ApoM Regulation of Vascular Tone and Hypertension Via Sphingosine-1-Phosphate.
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DOI：
10.1161/jaha.121.021261
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发表时间：
2021-07-20
影响因子：
5.4
通讯作者：
Di Lorenzo A
中科院分区：
文献类型：
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作者：
Del Gaudio I;Rubinelli L;Sasset L;Wadsack C;Hla T;Di Lorenzo A
大多数循环中的鞘氨醇-1-磷酸(S1P)与高密度脂蛋白(HDL)的载脂蛋白M(ApoM)结合，并通过G蛋白偶联的S1P受体介导高密度脂蛋白对血管系统的许多有利作用。高密度脂蛋白结合的S1P在动脉粥样硬化、心肌梗死和糖尿病中减少。除了作为靶点，内皮细胞也是S1P的来源，S1P由Spinster-2转运到细胞外，有助于循环S1P以及局部信号。缺乏内皮S1P受体1的小鼠是高血压，提示S1P信号的血管保护作用。本研究探讨内皮来源的S1P和载脂蛋白结合的S1P在调节血管张力和血压中的作用。ApoM基因敲除(Apom KO)小鼠和血管内皮细胞Spinster-2缺失(ECKO-Spns2)小鼠静脉注射血管紧张素II 28天。ECCO-Spns2和apom KO的血压通过遥测和尾袖测量，在基线和血管紧张素II之后，与对照组相比显著升高。值得注意的是，ECCO-Spns2表现出对血流的血管扩张受损和血压下降，这在临床上与心血管事件的风险增加有关。在高血压患者中，两组患者都表现出血流介导的血管扩张功能减弱，内皮细胞NO产生受到一定程度的损害，这一点在ECCO-Spns2中表现得更为明显。与对照组相比，ECCO-Spns2和apom KO小鼠高血压增加与心肌肥厚恶化相关。我们的研究发现Spinster-2和apom-HDL通过S1P-NO信号在血压动态平衡中发挥重要作用，并剖析了内皮来源的S1p和apom在高血压和心肌肥厚中的病理生理影响。
Most of the circulating sphingosine‐1‐phosphate (S1P) is bound to ApoM (apolipoprotein M) of high‐density lipoprotein (HDL) and mediates many beneficial effects of HDL on the vasculature via G protein–coupled S1P receptors. HDL‐bound S1P is decreased in atherosclerosis, myocardial infarction, and diabetes mellitus. In addition to being the target, the endothelium is a source of S1P, which is transported outside of the cells by Spinster‐2, contributing to circulating S1P as well as to local signaling. Mice lacking endothelial S1P receptor 1 are hypertensive, suggesting a vasculoprotective role of S1P signaling. This study investigates the role of endothelial‐derived S1P and ApoM‐bound S1P in regulating vascular tone and blood pressure. ApoM knockout (ApoM KO) mice and mice lacking endothelial Spinster‐2 (ECKO‐Spns2) were infused with angiotensin II for 28 days. Blood pressure, measured by telemetry and tail‐cuff, was significantly increased in both ECKO‐Spns2 and ApoM KO versus control mice, at baseline and following angiotensin II. Notably, ECKO‐Spns2 presented an impaired vasodilation to flow and blood pressure dipping, which is clinically associated with increased risk for cardiovascular events. In hypertension, both groups presented reduced flow‐mediated vasodilation and some degree of impairment in endothelial NO production, which was more evident in ECKO‐Spns2. Increased hypertension in ECKO‐Spns2 and ApoM KO mice correlated with worsened cardiac hypertrophy versus controls. Our study identifies an important role for Spinster‐2 and ApoM‐HDL in blood pressure homeostasis via S1P‐NO signaling and dissects the pathophysiological impact of endothelial‐derived S1P and ApoM of HDL‐bound S1P in hypertension and cardiac hypertrophy.