SH2 domain protein E (SHE) and ABL signaling regulate blood vessel size

Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number, enlarged lumen size and defects in blood flow and vessel elasticity, eventually leading to vessel collapse. ScRNA-seq analysis identified a set of novel genes which are differentially expressed in she mutants. Vascular endothelial specific overexpression of she was sufficient to restrict the vessel size. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar restriction of vessel diameter, suggesting that She might act as a negative regulator of Abl signaling. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes and increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.