An organ-specific angiogenic control mechanism for endothelial tailoring.

Each organ of the human body requires locally-adapted blood vessels1–3. The gain of such organotypic vessel specializations is often deemed molecularly unrelated to the process of organ vascularization. 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 signals4–6. The control mechanism relies on Wnt7a/b-dependent expression of Mmp25 in brain endothelial cells. This hitherto poorly characterized GPI-anchored matrix metalloproteinase is selectively required in endothelial tip cells to enable their initial migration across the pial basement membrane which lines the brain surface, and whose distinctive molecular composition is controlled by embryonic pial fibroblasts. Mechanistically, Mmp25 confers brain invasive competence by cleaving the pial basement membrane-enriched Col4a5/6 within a short non-collagenous region of the central helical part of the heterotrimer. Upon genetic interference with pial basement membrane composition, the Wnt/β-catenin-dependent organotypic control of brain angiogenesis is lost, resulting in a properly patterned, yet blood-brain barrier-defective cerebrovasculature. This work reveals an organ-specific angiogenesis mechanism, sheds light on tip cell mechanistic angiodiversity, and thereby illustrates how organs, by imposing local constraints on angiogenic tip cells, can select vessels matching their distinctive physiological requirements.