Angiogenic sprouting relies on collective migration and coordinated rearrangements of endothelial leader and follower cells. VE-cadherin-based adherens junctions have emerged as key cell-cell contacts that transmit forces between cells and trigger signals during collective cell migration in angiogenesis. However, the underlying molecular mechanisms that govern these processes and their functional importance for vascular development still remain unknown. We previously showed that the F-BAR protein PACSIN2 is recruited to tensile asymmetric adherens junctions between leader and follower cells. Here we report that PACSIN2 mediates the formation of endothelial sprouts during angiogenesis by coordinating collective migration. We show that PACSIN2 recruits the trafficking regulators EHD4 and MICAL-L1 to the rear end of asymmetric adherens junctions to form a recycling endosome-like tubular structure. The junctional PACSIN2/EHD4/MICAL-L1 complex controls local VE-cadherin trafficking and thereby coordinates polarized endothelial migration and angiogenesis. Our findings reveal a molecular event at force-dependent asymmetric adherens junctions that occurs during the tug-of-war between endothelial leader and follower cells, and allows for junction-based guidance during collective migration in angiogenesis.

血管新生依赖于内皮细胞的前导细胞和跟随细胞的集体迁移和协调的重排。基于VE-钙黏着蛋白的粘附连接已作为关键的细胞间接触出现，该接触在血管生成过程中的集体细胞迁移过程中在细胞之间传递力并触发信号。然而，控制这些过程的潜在分子机制及其对血管发育的功能重要性仍然未知。我们以前表明F-BAR蛋白PACSIN2被募集到前导细胞和跟随细胞之间的拉伸不对称粘附连接。在这里我们报告说，PACSIN2通过协调集体迁移来介导血管生成过程中内皮芽的形成。我们表明，PACSIN2募集人口贩运监管机构EHD4和MICAL-L1到不对称粘附连接的后端，以形成一个回收的内体样管状结构。连接的PACSIN2 / EHD4 / MICAL-L1复合体控制局部VE-钙粘蛋白的运输，从而协调极化的内皮迁移和血管生成。我们的发现揭示了在分子依赖的不对称粘附连接处发生的分子事件，该事件发生在内皮细胞前导细胞和跟随细胞之间的拔河比赛中，并允许在血管生成过程中的集体迁移过程中进行基于连接的指导。