Bright Afranie

United States

Role of hypoxia in coronary angiogenesis: Hypoxia stimulate SOX17-mediated- but repress APJ-mediated-Coronary Angiogenesis in developing mouse heart

Bright O. Afranie, Chhiring Sherpa, Bryce Kushal, Alyx Panoncillo, Ken Reed, Felix Addo, Rupak Parajuli, and Bikram Sharma, PhD.

1.Department of Biology, Ball State University, Muncie, IN, USA

Abstract

Background

Coronary Artery Disease (CAD) is a significant contributor to global modality, with a particularly profound impact in the United States. The intricate process of coronary aery development begins with the formation of the endothelium during embryonic stages. Sox17 and APJ signaling regulate compensatory coronary angiogenesis in the developing mouse heart. Sox17 is hypothesized to stimulate endocardium-derived coronary angiogenesis, whereas APJ mediates angiogenic signaling pathways essential for coronary growth from the sinus venosus. Furthermore, hypoxia is also implicated as an important signal in mediating endocardium-derived compensatory angiogenesis in APJ mutant heart. However, the interplay between APJ, hypoxia, and SOX17 signaling pathways in the regulation of coronary angiogenesis is not fully understood.

Methods

In this study, we established a hypoxia gain-of-function mouse model system to investigate whether hypoxia interacts with APJ and SOX17 to regulate coronary angiogenesis. We utilized the Nkx2.5Cre+ER inducible deletion Cre line and the vhl flox/flox mouse line to delete the vhl gene in cardiac progenitor cells and early cardiomyocytes. By depleting VHL protein and stabilizing Hif1alpha, this approach successfully mimicked hypoxic conditions in developing mouse hearts.

Results

Our results demonstrated that HIF-1α protein levels were significantly (p<0.05) elevated in cKO samples, confirming the effectiveness of the hypoxia model. There was a significant downregulation of APJ mRNA levels (p<0.05) and protein (p<0.05) expression and a trend showing upregulation of SOX17 expression under hypoxic conditions.

Conclusions

These findings support the hypothesis that myocardial hypoxia modulates coronary vessel development by repressing APJ and potentially enhancing SOX17 signaling. This study provides valuable insights into the molecular mechanisms underlying coronary angiogenesis and highlights potential therapeutic targets for CAD.