ABSTRACT Heart failure (HF) is a leading cause of morbidity and mortality in the US and its prevalence is expected to rise with the aging of the general population. Myocardial infarction (MI), chronic cardiac overload or valvular diseases often lead to the loss of cardiomyocytes (CMs). However, the limited endogenous proliferation capacity of adult CM impedes CM renewal and contributes to the development of HF. Interestingly, recent studies indicate that hypoxia promotes CM proliferation and improves recovery after myocardial injury, suggesting that endogenous pathways involved in CM proliferation can be activated and are sufficient to induce CM renewal without genetic manipulation in both healthy and diseased hearts. Therefore, promotion of endogenous CM renewal is a promising therapeutic approach to treat HF. However, the mechanisms involved in hypoxia-induced CM proliferation remain largely unknown. Prolyl hydroxylase domain proteins (PHDs) are widely considered as the oxygen sensors. Whether PHDs are involved in hypoxia-induced CM proliferation and renewal is unknown. Further, endothelial cells (ECs) act as the “first-responder” to environmental cues such as oxygen and nutrients. It is unclear whether cardiac EC-CM communication plays a role in hypoxia-induced CM proliferation. Therefore, exploring the role of endothelial PHDs in CM proliferation is of critical importance for understanding the basic mechanisms involved in endogenous CM renewal and will provide us novel approaches to treat HF. We have recently demonstrated that EC-specific knockout (eKO) of PHD2/3 promoted CM proliferation, improved cardiac function, and prevented ventricular failure induced by MI. Mechanistically, we discovered that yes-associated protein (YAP), a key player of organ size control and CM proliferation, was specifically activated in CMs of PHD2/3 eKO mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that apelin (Apln), a GPCR ligand, was markedly upregulated in cardiac ECs of PHD2/3 eKO mice via HIF-2a. We further demonstrated that Apln potently activated YAP in CMs and promoted CM proliferation. Notably, deletion of HIF- 2a or Apln in ECs eliminated the beneficial effects on cardiac function observed in PHD2/3 eKO mice. More importantly, CM-specific deletion of Apln receptor (AplnR) in mice at neonatal or adult stages inhibited YAP activation and deteriorated heart function. These data lead us to hypothesize that an endothelial PHD-mediated paracrine mechanism plays a key role in CM proliferation and renewal via Apln/AplnR pathway. To test this hypothesis, we will elucidate the underlying molecular mechanism by which endothelial PHD-mediated paracrine pathways regulate Hippo-YAP signaling in CMs. In addition, we will study the essential role of Apln/AplnR pathway in CM proliferation and normal heart function. Last, we will investigate the role of Apln/AplnR pathway in mouse models of heart failure.