The coronary vascular system is a dense network of arteries, veins and capillaries that provides the blood supply to the heart, and thus its formation and function are crucial for efficient cardiac function. Whilst hypoxia is a known stimulus for the growth of new vessels by sprouting angiogenesis in development and disease, the mechanisms underlying neovascular growth in response to developmental and injury-induced hypoxia in the heart remain poorly understood.

We previously identified three independent transcriptional pathways that regulate different aspects of coronary vessel growth during development and following neonatal injury, but are not reactivated following myocardial infarction (MI) in the adult murine heart. We are now investigating the specific consequences of myocardial hypoxia on these developmental pathways using a cardiomyocyte-specific knockdown of the Phd2 gene. In this model, the hypoxia-responsive HIF pathway is ectopically stabilised, resulting in the induction of the HIF-dependent transcriptional response in the myocardium. This hypoxic environment results in expansion of endocardial-derived angiogenic sprouting, whilst establishment of the sinus-venosus (SV) derived vascular plexus is largely unaffected. However, patterning of the SV-derived coronary veins and the transition of venous to arterial endothelial cells to form the coronary arteries appears to be disrupted. Single cell RNA sequencing on the developing coronary ECs is now being used to identify underlying transcriptional changes that are contributing to these phenotypes.