Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Elife. 2019 Nov 25;8:e49405. doi: 10.7554/eLife.49405.
The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA). We show that BBB permeability to small molecules increases in mice. Vesicle-mediated transfer of albumin in arterioles increased 3 to 10-fold in mice, whereas transcytosis in capillaries and venules remained unchanged. The S1P receptor 1 agonist SEW2871 rapidly normalized paracellular BBB permeability in mice, and inhibited transcytosis in penetrating arterioles, but not in pial arterioles. Thus, apoM-bound S1P maintains low paracellular BBB permeability in all cerebral microvessels and low levels of vesicle-mediated transport in penetrating arterioles.
血脑屏障（BBB）由脑微血管内皮细胞形成，但血液传播的信号分子如何影响通透性尚不完全清楚。我们使用载脂蛋白 M（apoM）结合的鞘氨醇 1-磷酸（S1P）信号通路来研究不同类别的脑微血管中的 apoM 缺失小鼠（）中 S1P 信号通路如何影响 BBB。我们使用双光子显微镜监测了钠荧光素（376 Da）、Alexa Fluor（643 Da）和荧光白蛋白（45 kDa）的 BBB 通透性。我们发现，apoM 缺失小鼠的小分子 BBB 通透性增加。载脂蛋白 M 缺失小鼠的小动脉中，白蛋白的囊泡介导转运增加了 3 到 10 倍，而毛细血管和小静脉中的转胞吞作用保持不变。S1P 受体 1 激动剂 SEW2871 可迅速使 apoM 缺失小鼠的细胞旁 BBB 通透性正常化，并抑制穿透性小动脉中的转胞吞作用，但不抑制软脑膜小动脉中的转胞吞作用。因此，apoM 结合的 S1P 可维持所有脑微血管中的低细胞旁 BBB 通透性和穿透性小动脉中的低囊泡介导转运。
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