Myovascular Mechanisms of Cardiac Growth and Regeneration

ABSTRACT: We, and others, have determined that cardiomyocyte (CM) proliferation is dependent on cardiac endothelial cells (CECs). Proliferating CECs are spatiotemporally coupled to proliferating CMs in the neonatal mouse heart; loss of CECs leads to decreased CM proliferation; and higher levels of the master angiogenic factor Vegfa promote cardiac growth in zebrafish, neonatal mice, and humans. Based on these studies, our overall hypothesis is that activated, proliferating CECs instruct CM proliferation. Here, we propose studies to determine how CECs promote CM proliferation. We will use scRNA-seq and spatial modeling to identify the specific subset of CECs physically associated with proliferating CMs; we will determine how Ezh2- mediated chromatin remodeling coordinates CEC activation with CM proliferation; and we will define the potency of CEC-induced growth factors to stimulate CM proliferation. This work will result in new cellular, epigenetic, and paracrine mechanisms for CEC-induced cardiac growth and has high potential to inform methods for therapeutic heart regeneration.