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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, <jats:italic>apelin receptor b<\/jats:italic> (<jats:italic>aplnrb<\/jats:italic>) expression closely mirrors that of the canonical fenestrated endothelium marker, <jats:italic>plasmalemma vesicle-associated protein b<\/jats:italic> (<jats:italic>plvapb<\/jats:italic>), highlighting <jats:italic>aplnrb<\/jats:italic> as a second marker for the fenestrated endothelium. However, our data indicate that Apelin signaling does not regulate expression of <jats:italic>plvapb<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1038\/s41467-025-63003-2","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T17:44:09Z","timestamp":1755625449000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Apelin as a CNS-specific pathway for fenestrated capillary formation in the choroid plexus"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2177-3382","authenticated-orcid":false,"given":"Lukas","family":"Herdt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7784-3474","authenticated-orcid":false,"given":"Stefan","family":"Baumeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0050-233X","authenticated-orcid":false,"given":"Jeshma","family":"Ravindra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1403-5805","authenticated-orcid":false,"given":"Jean","family":"Eberlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0427-5338","authenticated-orcid":false,"given":"Christian S. 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