Abstract
Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.
Highlights
A long-standing question in developmental and cell biology relates to how cells integrate mechanical and chemical signals to orchestrate the morphogenic behaviours that ensure adequate tissue patterning
yes-associated protein 1 (YAP) is required for endothelial cell proliferation in response to mechanical stretch As YAP and TAZ display pro-proliferative and anti-apoptotic roles in many cell types (Piccolo et al, 2014; Meng et al, 2016), we evaluated whether the reduced vascularization of Yap/Taz iEC-KO retinas was associated with reduced cell proliferation or increased apoptosis
The present study aimed to provide a detailed understanding of the distribution and function of endothelial YAP and TAZ in angiogenesis
Summary
A long-standing question in developmental and cell biology relates to how cells integrate mechanical and chemical signals to orchestrate the morphogenic behaviours that ensure adequate tissue patterning. The arrangement and distribution of cells rather than their numbers appear to drive morphogenesis of the vascular tree. Recent data showing unaltered remodelling in the absence of endothelial cell apoptosis and normal branching frequency across a range of endothelial cell densities support this idea (Watson et al, 2016). Too few cells will jeopardize network formation and stability (Phng et al, 2009), whereas too many cells might compromise vessel calibre control (Watson et al, 2016). Functional network formation needs to establish the right number of cells in the right place, and distribute them such that the
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