Intercellular Tension Negatively Regulates Angiogenic Sprouting of Endothelial Tip Cells via Notch1-Dll4 Signaling

Mechanical force plays pivotal roles in vascular development during tissue growth and regeneration. Nevertheless, the process by which mechanical force controls the vascular architecture remains poorly understood. Using a systems bioengineering approach, it is shown that intercellular tension negatively regulates tip cell formation via Notch1-Dll4 signaling in mouse retinal angiogenesis in vivo, sprouting embryoid bodies, and human endothelial cell networks in vitro. Reducing the intercellular tension pharmacologically by a Rho-associated protein kinase inhibitor or physically by single cell photothermal ablation of the capillary networks promotes the expression of Dll4, enhances angiogenic sprouting of tip cells, and increases the vascular density. Computational biomechanics, RNA interference, and single cell gene expression analysis reveal that a reduction of intercellular tension attenuates the inhibitory effect of Notch signaling on tip cell formation and induces angiogenic sprouting. Taken together, the results reveal a mechanoregulation scheme for the control of vascular architecture by modulating angiogenic tip cell formation via Notch1-Dll4 signaling.