Endocardial Tie2 orchestrates cardiac trabeculation via sequestering FOXO1 within the cytoplasm and stimulating versican cleavage

Conversely, excessive PI3K signaling (the direct regulator of phosphorylation of AKT) in EdCs caused cardiac hypotrabeculation. Further, we identify that endocardial loss of Tie2 resulted in impaired cleavage of versican, which was associated with enhanced expression of ADAMTS endogenous inhibitor TIMP3 in Tie2-cko EdCs. Thus, our results suggest that TIE2 signaling in the early embryonic endocardium promotes endocardial growth via sequestering FOXO1 within the cytoplasm and modulates cardiomyocyte proliferation via stimulating versican cleavage to orchestrate myocardial trabeculation, providing insights into the pathogenesis of CHD.