Hypoxia regulate developmental coronary angiogenesis potentially through VEGF-R2- and SOX17-mediated signaling

The development of coronary vessels in embryonic mouse heart involves various progenitor populations, including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is known to regulate coronary growth from the SV, whereas VEGF-A/VEGF-R2 signaling controls growth from the endocardium. Previous studies suggest hypoxia might regulate coronary growth, but its specific downstream pathways are unclear. In this study, we further investigated the role of hypoxia and have identified SOX17- and VEGF-R2-mediated signaling as the potential downstream pathways in its regulation of developmental coronary angiogenesis.

HIF-1α stabilization by knocking out von Hippel Lindau (VHL) protein in the myocardium (cKO) disrupted normal coronary angiogenesis in embryonic mouse hearts, resembling patterns of accelerated coronary growth. VEGF-R2 expression was increased in coronary endothelial cells under hypoxia in vitro and in VHL cKO hearts in vivo. Similarly, SOX17 expression was increased in the VHL cKO hearts, while its knockout in the endocardium disrupted normal coronary growth.

These findings provide further evidence that hypoxia regulates developmental coronary growth potentially through VEGF-R2 and SOX17 pathways, shedding light on mechanisms of coronary vessel development.