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^3,4,5. 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.

脊椎动物器官需要局部适应的血管^1,2。这种器官型血管特化的获得通常被认为在分子上与器官血管化过程无关。在这里，与这个模型相反，我们揭示了大脑特异性血管生成的分子机制，该机制在 Wnt7a/b 配体（众所周知的血脑屏障成熟信号）的控制下运行^3,4,5。该控制机制依赖于 Mmp25 的 Wnt7a/b 依赖性表达，我们发现 Mmp25 在脑内皮细胞中富集。斑马鱼中的 CRISPR-Cas9 诱变表明，内皮尖端细胞选择性地需要这种特征不明的糖基磷脂酰肌醇锚定基质金属蛋白酶，以使其能够最初迁移穿过大脑表面的软脑膜基底膜。从机制上讲，Mmp25 通过在异源三聚体中央螺旋部分的短非胶原区域内裂解脑膜成纤维细胞衍生的 IV 型胶原 α5/6 链，赋予脑侵袭能力。在对软脑膜基底膜组成进行遗传干扰后，Wnt-β-连环蛋白依赖性脑血管生成的器官型控制丧失，导致脑血管系统结构正常，但血脑屏障有缺陷。我们揭示了器官特异性的血管生成机制，阐明了尖端细胞机制的血管多样性，从而说明器官如何通过对血管生成尖端细胞施加局部限制来选择符合其独特生理需求的血管。