A brain-specific angiogenic mechanism enabled by tip cell specialization

Giel Schevenels, Pauline Cabochette, Michelle America, Arnaud Vandenborne, Line De Grande, Stefan Guenther, Liqun He, Marc Dieu, Basile Christou, Marjorie Vermeersch, Raoul F. V. Germano, David Perez-Morga, Patricia Renard, Maud Martin, Michael Vanlandewijck, Christer Betsholtz and Benoit Vanhollebeke ()
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Giel Schevenels: Université libre de Bruxelles (ULB)
Pauline Cabochette: Université libre de Bruxelles (ULB)
Michelle America: Université libre de Bruxelles (ULB)
Arnaud Vandenborne: Université libre de Bruxelles (ULB)
Line De Grande: Université libre de Bruxelles (ULB)
Stefan Guenther: ECCPS Bioinformatics and Deep Sequencing Platform
Liqun He: Uppsala University
Marc Dieu: University of Namur
Basile Christou: Université libre de Bruxelles (ULB)
Marjorie Vermeersch: Université libre de Bruxelles (ULB)
Raoul F. V. Germano: Université libre de Bruxelles (ULB)
David Perez-Morga: Université libre de Bruxelles (ULB)
Patricia Renard: University of Namur
Maud Martin: Université libre de Bruxelles (ULB)
Michael Vanlandewijck: Uppsala University
Christer Betsholtz: Uppsala University
Benoit Vanhollebeke: Université libre de Bruxelles (ULB)

Nature, 2024, vol. 628, issue 8009, 863-871

Abstract: Abstract Vertebrate organs require locally adapted blood vessels1,2. 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 signals3–5. 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 lining the brain surface. Mechanistically, Mmp25 confers brain invasive competence by cleaving meningeal fibroblast-derived collagen IV α5/6 chains within a short non-collagenous region of the central helical part of the heterotrimer. After genetic interference with the pial basement membrane composition, the Wnt–β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in properly patterned, yet blood–brain-barrier-defective cerebrovasculatures. We reveal an organ-specific angiogenesis mechanism, shed light on tip cell mechanistic angiodiversity and thereby illustrate how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.

Date: 2024
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DOI: 10.1038/s41586-024-07283-6

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