Herdt Lukas, Baumeister Stefan, Ravindra Jeshma, Eberlein Jean, Helker Christian S M
Department of Biology, Animal Cell Biology, Marburg University, Marburg, Germany.
Nat Commun. 2025 Aug 19;16(1):7729. doi: 10.1038/s41467-025-63003-2.
The cerebral vasculature consists of a heterogenous network of blood vessels, including barrier-forming capillaries with blood-brain-barrier (BBB) properties and fenestrated capillaries specialized for molecular exchange. While key pathways regulating BBB vessel formation have been identified, the mechanisms driving fenestrated vessel development remain poorly understood. Here, we identify Apelin signaling as a critical, cell type-specific pathway required for the formation of fenestrated capillaries in the choroid plexus (CP), while being dispensable for angiogenesis and barriergenesis of adjacent BBB vessels. Notably, apelin receptor b (aplnrb) expression closely mirrors that of the canonical fenestrated endothelium marker, plasmalemma vesicle-associated protein b (plvapb), highlighting aplnrb as a second marker for the fenestrated endothelium. However, our data indicate that Apelin signaling does not regulate expression of plvapb. Furthermore, we identify a population of undifferentiated pre-programmed leptomeningeal fibroblast as the Apelin source, regulating fenestrated vessel formation in the CP. Utilizing our previously engineered APLNR-cpGFP conformational biosensor we map localized Apelin ligand hotspots across the brain, which guide the development of fenestrated blood vessels in the CP. Collectively, our findings uncover a meningeal-vascular signaling axis that promotes fenestrated vessel formation in the CP and is essential for establishing cerebrovascular heterogeneity.
脑脉管系统由一个异质性的血管网络组成，包括具有血脑屏障（BBB）特性的形成屏障的毛细血管和专门用于分子交换的有孔毛细血管。虽然调节血脑屏障血管形成的关键途径已被确定，但驱动有孔血管发育的机制仍知之甚少。在这里，我们确定阿片肽信号传导是脉络丛（CP）中有孔毛细血管形成所需的关键细胞类型特异性途径，而对相邻血脑屏障血管的血管生成和屏障形成则是可有可无的。值得注意的是，阿片肽受体b（aplnrb）的表达与经典的有孔内皮标记物质膜囊泡相关蛋白b（plvapb）的表达密切相关，突出了aplnrb作为有孔内皮的第二个标记物。然而，我们的数据表明阿片肽信号传导并不调节plvapb的表达。此外，我们确定了一群未分化的预编程软脑膜成纤维细胞作为阿片肽来源，调节脉络丛中有孔血管的形成。利用我们之前设计的APLNR-cpGFP构象生物传感器，我们绘制了全脑局部阿片肽配体热点图，这些热点引导脉络丛中有孔血管的发育。总的来说，我们的发现揭示了一个脑膜-血管信号轴，该轴促进脉络丛中有孔血管的形成，并且对于建立脑血管异质性至关重要。
