Abstract
The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we show that myocardium-derived angiopoietin-1 (Ang1) is essential for coronary vein formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Collectively, our results indicate that myocardial Ang1 positively regulates coronary vein formation presumably by promoting the proliferation, migration and differentiation of immature ECs derived from the SV.
Highlights
The origin and developmental mechanisms underlying coronary vessels are not fully elucidated
A more recent report suggested that endocardial endothelial cells (ECs) generate the endothelium of coronary arteries through myocardial– endothelial signalling by vascular endothelial growth factor-A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2)[11]
We previously found that neuregulin1(NRG-1)/ErbB signalling is essential for cardiac homeostasis presumably via Ang[1] secreted from cardiomyocytes[16]
Summary
The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Analysis of the sectioned samples clearly revealed subepicardial APJ-positive vessel structures in the control but not in the Ang1CKO embryos (Fig. 2e–h, Supplementary Fig. 3c,d), suggesting that cardiomyocyte-derived Ang[1] is required for the formation of subepicardial APJ-positive mature coronary veins.
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