Endothelin-1 signaling regulates chamber-specific mouse atrial cardiomyocyte cytokinesis and polyploidy

Cardiomyocyte (CM) maturation is a central process in postnatal heart development accompanied by profound structural, metabolic, and cell cycle changes. One hallmark of this maturation program is CM polyploidy that is closely associated with the loss of cardiac regenerative capacity. Most insights into ploidy regulation have come from studies of ventricular CMs, whereas the spatiotemporal dynamics and molecular regulation of atrial CM polyploidy remain poorly understood. We show that CM polyploidy in the postnatal mouse heart is highly chamber-specific, with >90% of ventricular CMs are polyploid, compared with [~]30% of left atrial (LA) CMs and [~]15% of right atrial (RA) CMs. These chamber-specific differences correlate with their differential susceptibility to cytokinesis failure and are regulated, at least in part, by endocardial cells. Mechanistically, we identify the endocardial/endothelial-derived factor EDN1 as a postnatally enriched signal in the LA compared with the RA. EDN1 can act directly on primary aCMs to inhibit cytokinesis, in part by suppressing Wnt signaling. Consistently, inhibition of Edn1 signaling in vivo using Bosentan reduced CM cytokinesis failure specifically in the LA. Altogether, our findings reveal a previously unrecognized role for endothelial-myocardial crosstalk in regulating chamber-specific CM polyploidy through Edn1 signaling.