Abstract
To create a closed vascular system, angiogenic sprouts must meet and connect in a process called vessel fusion, which is a prerequisite for establishment of 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) to enter a “ready‐to‐anchor” state. IMD promotes vascular endothelial cadherin (VEC) accumulation at the potential fusion site to facilitate anchoring of approaching vessels to each other. Simultaneously, IMD fine‐tunes VEC activity to achieve a dynamic balance between VEC complex dissociation and reconstitution in order to widen the anastomotic point. IMD induces persistent VEC phosphorylation. Internalized phospho‐VEC preferentially binds to Rab4 and Rab11, which facilitate VEC vesicle recycling back to the cell‐cell contact for reconstruction of the VEC complex. This novel mechanism may explain how neovessels contact and fuse to adjacent vessels to create a closed vascular system.
Highlights
IntroductionTo create a closed vascular system, angiogenic sprouts must meet and connect in a process called vessel anastomosis or vessel fusion, which is a prerequisite for blood flow through the vessels.[3,4] few studies have focused on the process of vessel fusion
We found that vascular endothelial cadherin (VEC) endosomes colocalized with either Rab[4] or Rab[11] in the cytoplasm of resting endothelial cells (ECs) (Figure 6A)
The results showed that IMD significantly promoted binding of internalized VEC to Rab4/Rab[11] (Figure 6F-H)
Summary
To create a closed vascular system, angiogenic sprouts must meet and connect in a process called vessel anastomosis or vessel fusion, which is a prerequisite for blood flow through the vessels.[3,4] few studies have focused on the process of vessel fusion. According to Fantin et al, macrophages act as cellular chaperones for vascular anastomosis.[7] the molecular machinery that stimulates and regulates vessel fusion remains largely unknown.[3,4] Our previous work[8,9,10] revealed that intermedin (IMD; named adrenomedullin 2 [ADM2]), a member of the calcitonin family,[11] normalizes the tumor vasculature and effectively improves tumor blood supply. Because IMD significantly reduces vessel density while increasing the number of anastomotic vessels,[9,10] we hypothesize that IMD may be an important molecule that stimulates vessel fusion, contributing to vessel normalization and blood perfusion improvement
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