Cdc42 Mediates Bmp-Induced Sprouting Angiogenesis through Fmnl3-Driven Assembly of Endothelial Filopodia in Zebrafish

During angiogenesis in vivo, endothelial cells (ECs) at the tips of vascular sprouts actively extend filopodia that are filled with bundles of linear actin filaments. To date, signaling pathways involved in the formation of endothelial filopodia have been studied using in-vitro-cultured ECs that behave differently from those in vivo. Herein, we have delineated a signaling pathway that governs the assembly of endothelial filopodia during angiogenic sprouting of the caudal vein plexus (CVP) in zebrafish. During CVP formation, bone morphogenetic protein induces the extension of endothelial filopodia and their migration via Arhgef9b-mediated activation of Cdc42. Active Cdc42 binds to and stimulates Formin-like 3, an actin-regulatory protein of the formin family, which, in turn, promotes the extension of endothelial filopodia to facilitate angiogenic sprouting of the CVP. Thus, this study has elucidated molecular mechanisms underlying the formation of endothelial filopodia and their role in angiogenesis in vivo.