Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P₁–S1P₅. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P₁ and S1P₃ mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P₂ is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

1-磷酸鞘氨醇 (S1P) 是一种生物活性脂质，可通过激活同源受体 S1P ₁ –S1P ₅来介导多种效应。过去 30 年对 S1P 调节通路的审查已经确定了大脑和脑血管系统中重要的、偶尔会抵消的功能。例如，虽然 S1P ₁和 S1P ₃介导对神经胶质细胞的促炎作用并直接促进内皮细胞屏障的完整性，但 S1P ₂具有抗炎作用，但会破坏屏障完整性。累积起来，有重要的临床前证据表明该途径在调节导致脑血管疾病和血管性痴呆的过程中发挥关键作用，这两者都是血管性认知障碍 (VCI) 连续体的一部分。这得到了临床研究的支持，这些研究已经确定了 S1P 的改变与认知缺陷之间的相关性。我们回顾了一些研究，这些研究提出并评估了潜在机制，通过这些机制，这种改变有助于病理性 S1P 信号传导，从而导致 VCI 相关的慢性神经炎症和神经变性。值得注意的是，S1P 受体具有不同但重叠的表达模式，并表现出复杂的相互作用。所以，S1P 产生的净效应代表了 S1P 受体对大脑神经、血管和免疫细胞的累加、协同或拮抗作用的累积贡献。最终，针对 S1P 信号的优化治疗策略将不得不考虑这些复杂的相互作用。