Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, D-48149, Muenster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Muenster, Germany.
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, E28029, Spain.
Dev Biol. 2022 Jun;486:26-43. doi: 10.1016/j.ydbio.2022.03.006. Epub 2022 Mar 23.
The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa had an impact on endothelial cell (EC) migration and proliferation. Surprisingly, mutations in vegfab more strongly affected EC proliferation in distinct blood vessels, such as intersegmental blood vessels in the zebrafish trunk and central arteries in the head. Analysis of downstream signaling pathways revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutant phenotypes in affected blood vessels. Together, these results suggest that extracellular matrix bound Vegfa might act through PI3K signaling to control EC proliferation in a distinct set of blood vessels during angiogenesis.
适当模式化的血管网络的形成需要内皮细胞的迁移和增殖。血管内皮生长因子 A（VEGFA）途径的信号传导对于协调这些过程至关重要。mRNA 剪接产生短（扩散）和长（细胞外基质结合）Vegfa 同种型。这些同种型在控制细胞功能方面的差异尚不清楚。在斑马鱼中，vegfaa 产生短和长同种型，而 vegfab 仅产生长同种型。我们发现 vegfaa 的突变对内皮细胞（EC）的迁移和增殖有影响。令人惊讶的是，vegfab 的突变在特定血管（如斑马鱼躯干中的节间血管和头部中的中央动脉）中对 EC 增殖的影响更为强烈。下游信号通路分析显示 MAPK（ERK）激活没有变化，而抑制 PI3 激酶信号通路则在受影响的血管中模拟了 vegfab 突变体表型。总之，这些结果表明细胞外基质结合的 Vegfa 可能通过 PI3K 信号通路在血管生成过程中控制特定一组血管中的 EC 增殖。
