Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling

Vitali, H. E.; Kuschel, B.; Sherpa, C.; Jones, B. W.; Jacob, N. S.; Madiha, S. A.; Elliott, S.; Dziennik, E.; Kreun, L.; Conatser, C.; Bhetwal, B. P.; Sharma, B.

doi:10.1101/2023.08.16.553531

bioRxiv · 10.1101/2023.08.16.553531

Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling

Vitali, H. E.·Kuschel, B.·Sherpa, C.·Jones, B. W.·Jacob, N. S.·Madiha, S. A.·Elliott, S.·Dziennik, E.·Kreun, L.·Conatser, C.·Bhetwal, B. P.·Sharma, B.

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Abstract

BackgroundCoronary vessels in embryonic mouse heart arises from multiple progenitor population including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is shown to regulate coronary growth from SV pathway within the subepicardium, whereas VEGF-A/VEGF-R2 pathways is implicated to regulate coronary growth from endocardium pathway. Our previous study show hypoxia as a potential signaling cue to stimulate overall coronary growth and expansion within the myocardium. However, the role of hypoxia and its downstream signaling pathways in the regulation of coronary vessel development is not known. In this study, we investigated the role of hypoxia in coronary vessel development and have identified SOX17- and VEGF-R2-mediated signaling as a potential downstream pathway of hypoxia in the regulation of coronary vessel development. ResultsWe show that hypoxia gain-of-function in the myocardium through upregulation of HIF-1 disrupts the normal pattern of coronary angiogenesis in developing mouse hearts and displays phenotype that is reminiscent of accelerated coronary growth. We show that VEGF-R2 expression is increased in coronary endothelial cells under hypoxia gain-of-function in vivo and in vitro. Furthermore, we show that SOX17 expression is upregulated in developing mouse heart under hypoxia gain-of-function conditions, whereas SOX17 expression is repressed under hypoxia loss-of-function conditions. Furthermore, our results show that SOX17 loss-of-function disrupts normal pattern of coronary growth. ConclusionCollectively, our data provide strong phenotypic evidence to show that hypoxia might regulate coronary growth in the developing mouse heart potentially through VEGF-R2- and SOX17-mediated downstream signaling pathways.

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Vitali, H. E., Kuschel, B., Sherpa, C., Jones, B. W., Jacob, N. S., Madiha, S. A., Elliott, S., Dziennik, E., Kreun, L., Conatser, C., Bhetwal, B. P., Sharma, B.. 2023-08-16. Hypoxia regulate developmental coronary angiogenesis potentially through VEGFR2- and SOX17-mediated signaling. https://doi.org/10.1101/2023.08.16.553531

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