Cardiac cells couple up in heart regeneration

Heart regeneration requires proliferation of cardiomyocytes (CMs) – muscle cells that coordinate contractile forces of the heartbeat. This process also requires cardiac endothelial cells (CECs), which rapidly respond to injury by proliferating to extend nascent blood vessels into wound sites. However, how these two cell types interact to coordinate regenerative growth is unclear. In this study, Ravi Karra and colleagues profile the proliferation kinetics of CMs and CECs in mouse neonatal heart growth and regeneration, showing that they are spatiotemporally coupled. Here, this relationship hinges on vascular endothelial growth factor A (VEGFA) secreted from CMs, which act on CECs expressing the receptor VEGFR2: genetic deletion of Vegfr2 from CECs or VEGFA inhibition impairs proliferation of both cell types. Interestingly, in cryoinjury (a model of incomplete regeneration), these processes are decoupled and coordinated repair is attenuated. Regeneration can be enhanced, however, by boosting CEC density after cryoinjury using a virus encoding Vegfa. Finally, the authors show that circulating VEGFA levels correlate with human myocardial mass, suggesting VEGFA also stimulates cardiac developmental growth. Together, these findings demonstrate the VEGFA-VEGFR2 axis is crucial in coupling CM and CEC expansion during growth and regeneration, and reveal a myovascular ‘niche’ that may be of therapeutic interest in heart regeneration.