Aims Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for the endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet, as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC autonomous S1P production, it is unclear if relative reductions in circulating S1P can cause endothelial dysfunction. It is also unclear how EC S1PR1 insufficiency, whether induced by deficiency in circulating ligand or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets. Methods and results We here fine map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell-type–specific and relative deficiencies in S1P production to define ligand source and dose dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries, and a subset of high-endothelial venules (HEVs). Similar zonation was observed for albumin extravasation in EC S1PR1-deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic ECs, S1PR1 engagement was high in collecting vessels and lymph nodes and low in blind-ended capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signalling in lymphatics and HEV, haematopoietic cells provided ∼90% of plasma S1P and sustained signalling in resistance arteries and lung capillaries. S1PR1 signalling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages. Conclusion This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.

中文翻译：

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血液和淋巴管系统中鞘氨醇 1-磷酸受体-1 信号的分区、配体和剂量依赖性


目的 在与内皮功能障碍相关的疾病状态下，1-磷酸鞘氨醇 （S1P） 的循环水平降低，S1P 是内皮细胞 （EC） 保护性 S1P 受体-1 （S1PR1） 的 HDL 相关配体。然而，由于 S1PR1 对 S1P 具有高亲和力，并且可以通过配体非依赖性机制和 EC 自主 S1P 产生激活，因此尚不清楚循环 S1P 的相对减少是否会导致内皮功能障碍。目前还不清楚 EC S1PR1 功能不全，无论是由循环配体缺陷诱导还是由 S1PR1 定向免疫抑制治疗诱导，如何影响不同的血管亚群。方法和结果我们在这里精细绘制了小鼠血液和淋巴管系统中 S1PR1 信号的分区，叠加了 S1P 产生中的细胞类型特异性和相对缺陷，以确定配体来源和剂量依赖性，并将受体参与与基本功能相关联。在幼稚血管中，尽管表达广泛，但 EC S1PR1 参与仅限于电阻大小的动脉、肺毛细血管和高内皮小静脉 （HEV） 的子集。在 EC S1PR1 缺陷小鼠中观察到白蛋白外渗的类似分区，并且动脉选择性 S1pr1 缺失再现了脑外渗。在淋巴 EC 中，S1PR1 在集合血管和淋巴结中的参与度很高，而在引流组织液的盲端毛细血管中参与度较低。虽然 EC S1P 的产生维持了淋巴管和 HEV 中的 S1PR1 信号传导，但造血细胞提供了 ∼90% 的血浆 S1P 并在阻力动脉和肺毛细血管中持续信号传导。S1PR1 信号传导和内皮功能都对血浆 S1P 的减少非常敏感，表观饱和度约为正常水平的 50%。 S1PR1 参与不取决于性别或年龄，但在高血压和糖尿病患者的动脉中适度增加。鞘氨醇激酶 （Sphk）-2 缺陷还选择性地增加了动脉中 S1PR1 的参与，这可能归因于 Sphk1 依赖性 S1P 从血管周围巨噬细胞释放。结论 本研究强调了血管亚型 特异性 S1PR1 的功能和参与机制，并支持 S1P 作为内皮功能的循环生物标志物的相关性。