Coupled myovascular expansion directs cardiac growth and regeneration

Abstract

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.

The role of Vegfc signaling during cardiac regeneration in zebrafish

“…Along the same line of observations, stabilizing vessel-like structures in the non-regenerating medaka hearts after cardiac injury, significantly reduced scarring (Lai et al, 2017;Marín-Juez et al, 2019). Similarly, enhancing collateral formation in adult mouse hearts after MI results in a significant improvement in cardiac function (Das et al, 2019;Debenedittis et al, 2021). All of these data and observations emphasize the important role of coronary revascularization in promoting cardiac regeneration after cardiac injury.…”

“…Indeed a recent study by Das and colleagues revealed that CXCR4 is a main player promoting the formation of these collaterals in the regenerating neonatal mouse heart, and that inducing collateral formation in the adult mouse heart resulted in a significant functional improvement following MI (Das et al, 2019). Moreover, it has been recently shown that improving coronary revascularization in the adult mouse heart, stimulates CM proliferation (Debenedittis et al, 2021). All of these data suggest that coronaries are a vital factor that contributes to the regenerative outcome following injury.…”

“…As previously outlined, one of the important causes contributing to the mammalian's heart reduced capacity to regenerate is its poor revascularization potential, and that promoting coronary revascularization can promote cardiac regeneration and functional improvement in non-regenerative models (Debenedittis et al, 2021;Habib et al, 1991;Kocijan et al, 2021). These observations motivated many researchers to explore and identify factors that can promote this process.…”

“…Due to their highly potent role in promoting angiogenesis, VEGF family members were the center of investigations in attempts to promote coronary revascularization. Recent work has shown that overexpressing Vegfa in adult mouse hearts increased coronary revascularization and CM proliferation following MI (Debenedittis et al, 2021).…”

“…Deleting Vegfr2 results in a reduction in coronary endothelial cell (cEC) and cardiomyocyte (CM) proliferation. Conversely, overexpressing Vegfr2 increased cEC density and enhanced cardiac regeneration (Debenedittis et al, 2021). Moreover, stabilizing vessel-like structures in medaka, a fish species without cardiac regenerative capacity resulted in a reduction in scarring following cardiac injury (Lai et al, 2017).…”