Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling

Abstract

Abstract Blood vessel formation relies on biochemical and mechanical signals, particularly in sprouting angiogenesis where endothelial tip cells (TCs) guide sprouting through filopodia formation. The role of BMP receptors in defining endothelial tip-cell characteristics remains unclear. Our study elucidates the pivotal role of BMPR2 in actin-driven filopodia formation and mechanical properties of endothelial cells (ECs). Targeting bmpr2b in zebrafish impairs sprouting angiogenesis, while BMPR2-deficient human ECs diminished filopodia, impacting cell migration and actomyosin localization. Spheroid assays reveal reduced sprouting in fibrin gels, and in mosaic spheroids, BMPR2-deficient ECs fail to acquire tip-cell positions. Surprisingly, 3D traction force microscopy shows no significant differences in force-induced matrix deformations from BMPR2-deficient tip cells, which instead adopt a distinct cone-shaped morphology. BMPR2 localizes near filopodia interacting with BORG5 to regulate CDC42. Our findings unveil BMPR2 as a central hub integrating biochemical and biomechanical processes crucial for endothelial tip cells during angiogenesis.