Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P₁) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P₁ functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P₁ desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P_1, could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P₁, SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P₁ on endothelium without causing receptor desensitization and potently activated protection pathways in human endothelial cells. In a pig model of coronary endothelial damage, SAR247799 improved the microvascular hyperemic response without reducing lymphocyte numbers. Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P₁-desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P₁ functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P₁. These findings demonstrate that sustained S1P₁ activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability.

内皮功能障碍是组织损伤的标志，据信可引发血管疾病的发展。鞘氨醇-1 磷酸受体-1 (S1P ₁ ) 在内皮功能和淋巴细胞归巢中起着基本的生理作用。当前可用的靶向该受体的临床分子具有脱敏作用，并且本质上是导致淋巴细胞减少的S1P ₁功能性拮抗剂。它们在临床上有益于自身免疫性疾病，如多发性硬化症。在患者中，S1P ₁脱敏的几种副作用归因于内皮损伤，这表明具有相反作用的药物，即激活 S1P ₁的能力_，有助于恢复内皮稳态。我们发现并表征了 S1P ₁的偏向激动剂SAR247799，与 β-抑制蛋白和内化信号通路相比，其优先激活下游 G 蛋白信号传导的程度更大。SAR247799 激活内皮上的S1P ₁而不引起受体脱敏，并有效激活人内皮细胞中的保护通路。在冠状动脉内皮损伤的猪模型中，SAR247799 在不减少淋巴细胞数量的情况下改善了微血管充血反应。类似地，在肾缺血/再灌注损伤的大鼠模型中，SAR247799 在不诱导 S1P _{1 的}剂量下保留了肾脏结构和功能- 脱敏作用，如淋巴细胞减少和肺血管渗漏。相比之下，临床上使用的 S1P ₁功能性拮抗剂辛波莫德只能提供最小的肾脏保护并使 S1P ₁脱敏。这些发现表明，持续的 S1P ₁激活可以在不损害免疫反应的情况下在药理学上发生，为治疗与内皮功能障碍和血管通透性过高相关的疾病提供了一种新方法。