biostudies-literatureSchevenels GEuropean Research Council863-871https://www.ebi.ac.uk/biostudies/studies/S-EPMC11041701biostudies-literatureUnknown628(8009)Vertebrate organs require locally adapted blood vessels^1,2. The gain of such organotypic vessel specializations is often deemed to be molecularly unrelated to the process of organ vascularization. Here, opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis that operates under the control of Wnt7a/b ligands-well-known blood-brain barrier maturation signals^3-5. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25, which we find is enriched in brain endothelial cells. CRISPR-Cas9 mutagenesis in zebrafish reveals that this poorly characterized glycosylphosphatidylinositol-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane liniNatureA brain-specific angiogenic mechanism enabled by tip cell specialization.PMC11041701865176Dieu MVandenborne ADe Grande LVermeersch MVanlandewijck MHe LChristou BAmerica MGuenther SGermano RFVVanhollebeke BSchevenels GPerez-Morga DMartin MCabochette PRenard PBetsholtz CfalseA brain-specific angiogenic mechanism enabled by tip cell specialization.Vertebrate organs require locally adapted blood vessels^1,2. The gain of such organotypic vessel specializations is often deemed to be molecularly unrelated to the process of organ vascularization. Here, opposing this model, we reveal a molecular mechanism for brain-specific angiogenesis that operates under the control of Wnt7a/b ligands-well-known blood-brain barrier maturation signals^3-5. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25, which we find is enriched in brain endothelial cells. CRISPR-Cas9 mutagenesis in zebrafish reveals that this poorly characterized glycosylphosphatidylinositol-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane lini2024-01-01T00:00:00Z2024 Apr2026-06-01T21:54:22.166Z2025-04-06T03:15:37.637ZS-EPMC110417013857068710.1038/s41586-024-07283-6