Université de Paris, Paris Cardiovascular Research Centre, INSERM U970, France (A.N., M.P., A.B., T.M., G.A., V.B., L.C., A.C., H.N., P.-L.T., A.E., B.T., E.C.).
Institut des Vaisseaux et du Sang, Hôpital Lariboisière, France (M.P., P.-L.L.).
Circ Res. 2021 Feb 5;128(3):363-382. doi: 10.1161/CIRCRESAHA.120.316711. Epub 2020 Dec 2.
Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P modulation in stroke.
To address roles and mechanisms of engagement of endothelial cell S1P in the naive and ischemic brain and its potential as a target for cerebrovascular therapy.
Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P in the mouse brain. With an S1P signaling reporter, we reveal that abluminal polarization shields S1P from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion.
This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P agonists.
脑血管功能对大脑健康至关重要，内源性血管保护途径可能为神经紊乱提供治疗靶点。S1P（鞘氨醇 1-磷酸）信号在其他器官中协调血管功能，S1P（S1P 受体-1）调节剂包括 fingolimod，有望用于治疗缺血性和出血性中风。然而，S1P 也协调淋巴细胞的迁移，目前认为淋巴细胞是 S1P 调节在中风中的主要治疗靶点。
探讨内皮细胞 S1P 在未受刺激和缺血大脑中的作用和机制，及其作为脑血管治疗靶点的潜力。
我们使用 S1P 供应和信号的空间调节，证明了内皮细胞 S1P 在小鼠大脑中的关键血管保护作用。使用 S1P 信号报告基因，我们揭示了在血脑屏障成熟后，管腔外侧的极化使 S1P 免受循环内源性和合成配体的影响，将稳态信号限制在一小部分动脉内皮细胞中。S1P 信号维持了未受刺激大脑中的标志性内皮功能，并在缺血期间通过细胞自主的 S1P 供应而扩大。通过内皮细胞选择性缺乏 S1P 产生、输出或 S1P 受体来破坏这条途径，会显著加重永久性和短暂性缺血性中风模型中的脑损伤。相比之下，淋巴细胞 S1P 缺失引起的严重淋巴细胞减少症仅在再灌注的情况下提供适度的保护。在缺血性大脑中，内皮细胞 S1P 支持血脑屏障功能、微血管通畅性，并通过侧支吻合将血液重新引导至灌注不足的脑组织。通过补充药物与血脑屏障穿透性 S1P 选择性激动剂结合，以补充药物与血脑屏障穿透性 S1P 选择性激动剂结合，进一步增加内皮细胞受体池的药理学作用，可在治疗相关时间内独立于再灌注而进一步减少皮质梗死的扩张。
这项研究提供了遗传证据，支持内皮细胞在维持缺血半影区灌注和微血管通畅性方面发挥关键作用，这种作用是由 S1P 信号协调的，可以通过穿透血脑屏障的 S1P 激动剂进行神经保护。
