The ang1-tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) pathway is required for normal vascular development, but its molecular effectors are not well-defined during cardiac ontogeny. Here, we show that endocardial-specific attenuation of Tie2 results in midgestation lethality due to heart defects associated with a hyperplastic but simplified trabecular meshwork (fewer but thicker trabeculae). Reduced proliferation and production of endocardial cells following endocardial loss of Tie2 results in decreased endocardial sprouting required for trabecular assembly and extension. The hyperplastic trabeculae result from enhanced proliferation of trabecular cardiomyocytes, which is associated with upregulation of bone morphogenetic protein 10, increased retinoic acid (RA) signaling, and extracellular signal-regulated protein kinases 1 and 2 hyperphosphorylation in the myocardium. Intriguingly, myocardial phenotypes in conditional knockout hearts could be partially rescued by inhibiting in utero RA signaling with pan-RA receptor antagonist BMS493. These findings reveal 2 complementary functions of endocardial Tie2 during ventricular chamber formation: ensuring normal trabeculation by supporting endocardial cell proliferation and sprouting and preventing hypertrabeculation via suppression of RA signaling in trabecular cardiomyocytes.
Xianghu Qu, Cristina Harmelink, H. Scott Baldwin
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