Intermedin Promotes Vessel Fusion by Inducing Endothelial Cells into a 'Ready to Anchor' State

Abstract

To create a closed vascular system, angiogenic sprouts need to meet and connect in a process called vessel fusion, which is a prerequisite for establishing proper blood flow in nascent vessels. However, the molecular machinery underlying this process remains largely unknown. Herein, we report that intermedin (IMD), a calcitonin family member, promotes vessel fusion by inducing endothelial cells (ECs) into a “ready to anchor” state. IMD promotes VE-cadherin (VEC) accumulation at the potential fusion point to facilitate approaching vessels anchoring to each other. Simultaneously, IMD fine-tunes VEC activity to achieve a dynamic balance between VEC complex dissociation/reconstitution to widen the anastomotic point. IMD induces VEC endocytosis via Src-triggered VEC autophosphorylation, and concurrently promotes VEC endosome transport back to the cell-cell contact via Rab4 and Rab11 to rebuild the VEC complex. This novel mechanism may explain how the neovessels contact and fuse to adjacent vessels to create a closed vascular system