Innate heart regeneration in zebrafish and neonatal mammals requires multiple cell types, such as epicardial cells, nerves, and macrophages, to enable proliferation of spared cardiomyocytes (CMs). How these cells interact to create growth niches is unclear. Here we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that CM and CEC expansion is spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury, a model of incomplete regeneration, displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density in the border zone by injection of virus encoding Vegfa enhances CM proliferation and the efficacy of heart regeneration, suggesting that revascularization strategies to increase CEC numbers may be an important adjunct for approaches designed to promote CM proliferation after injury. Finally, we use a human Mendelian randomization study to demonstrate that circulating VEGFA levels are positively associated with higher myocardial mass among healthy individuals, suggesting similar effects on human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion for cardiomyogenesis and reveals the presence of a myovascular niche that underlies cardiac growth and regeneration.
Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.
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