Determining the role of elabela/APJ and apelin/APJ signaling on coronary endothelial cell proliferation, migration, and survival

Abstract

Coronary artery disease is one of the leading causes of death worldwide with no effective treatment. If we understand the cellular and molecular mechanisms of how these vessels are created at embryonic stages, then we can work towards creating therapeutic interventions. Apelin receptor (APJ) is an important regulator of coronary vessel formation in the embryonic mouse heart development, where it is known to function through its two ligands, ELABELA and APELIN. Coronary vessels develop through a process called angiogenesis, which involves cell proliferation, migration, and survival. Knockout studies in mice revealed that APJ signaling is important in regulating coronary angiogenesis from its progenitor cells. However, it is unclear how exactly APJ regulates coronary vessel formation through its dual ligands. Therefore, we aimed to investigate how APJ signaling from its two ligands regulate endothelial cell proliferation, migration, and survival during coronary angiogenesis. We hypothesized that ELABELA and APELIN both stimulate angiogenic behaviors of coronary endothelial cells when stimulated separately but inhibit each other’s ability to stimulate angiogenesis when activated together. We tested our hypothesis using an ex vivo explant culture model of coronary angiogenesis. Our results show that when explant cultures are stimulated by ELABELA and APELIN separately, both ELABELA and APELIN are found to stimulate proliferation, migration, and survival of coronary endothelial cells. However, we observed an inhibitory effect of ELABELA on APELIN’s ability to stimulate coronary angiogenesis when bound together. We also found that APELIN alone has more robust effect on coronary angiogenesis compared to ELABELA. Collectively, our results suggest that ELABELA and APELIN are both positive stimulator of coronary angiogenesis and they inhibit each other’s ability to stimulate angiogenic activity, potentially by competing for its common receptor, APJ.