Biomechanical control of vascular morphogenesis by the surrounding stiffness

Sprouting angiogenesis is a form of morphogenesis which expands vascular networks from preexisting networks. However, the precise mechanism governing efficient branch elongation driven by directional movement of endothelial cells (ECs), while the lumen develops under the influence of blood inflow, remains unknown. Herein, we show perivascular stiffening to be a major factor that integrates branch elongation and lumen development. The lumen expansion seen during lumen development inhibits directional EC movement driving branch elongation. This process is counter-regulated by the presence of pericytes, which induces perivascular stiffening by promoting the deposition of EC-derived collagen-IV (Col-IV) on the vascular basement membrane (VBM), thereby preventing excessive lumen expansion. Furthermore, inhibition of forward directional movement of the tip EC during lumen development is associated with decreased localization of the F-BAR proteins and Arp2/3 complexes at the leading front. Our results demonstrate how ECs elongate branches, while the lumen develops, by properly building the surrounding physical environment in coordination with pericytes during angiogenesis.