Three independent regulatory pathways involved in the development of the coronary vasculature are activated in the hearts of embryos and neonatal mice after myocardial infarction (MI) but repressed in adult mice. “[This finding] strongly indicates a fundamental divergence between the regulatory pathways intrinsically employed in the healthy and injured adult heart,” summarize the researchers.

Credit: V. Summersby/Springer Nature Limited

The generation of new coronary vessels after MI can attenuate ischaemic injury and cardiac dysfunction, but the mechanisms underlying vessel growth in the ischaemic heart are not well understood. The cellular processes involved in coronary vessel formation in the embryonic heart are well characterized, but whether these pathways can be reactivated in the adult heart is unclear. By analysing numerous gene enhancers that drive gene expression to endothelial cells of coronary vessels, Nicola Smart, Sarah De Val and colleagues identified three distinct signalling cascades implicated in coronary vessel growth.

First, sustained expression of the homeobox protein HLX3:lacZ transgene, which is activated by vascular endothelial growth factor A (VEGFA)–myocyte-specific enhancer factor 2 (MEF2) signalling in endothelial cells, was detected in both neonatal and adult endocardial-derived coronary vessels, confirming the role of this pathway in coronary vessel formation. Development of sinus venosus (SV)-derived coronary arteries required activation of the SOXF/RBPJ transcriptional programme. Finally, the bone morphogenetic protein (BMP)–mothers against decapentaplegic homologue (SMAD) pathway was found to be active in SV-derived coronary veins.

Importantly, after MI, all three pathways were activated in neonatal mouse hearts, which have regenerative potential, but repressed in the injured hearts of adult mice. “These findings were unexpected and highly relevant given that the VEGFA pathway has been the main pathway targeted in preclinical and clinical studies,” comments Smart.

the mechanisms underlying vessel growth in the ischaemic heart are not well understood

To conclude, these results indicate that distinct pathways are involved in neovascular growth during developmental coronary vessel formation and ischaemic injury.