Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4

Endocardial cells lining the heart lumen are coronary vessel progenitors during embryogenesis. Re-igniting this developmental process in adults could regenerate blood vessels lost during cardiac injury, but this requires additional knowledge of molecular mechanisms. Here, we use mouse genetics and scRNA-seq to identify regulators of endocardial angiogenesis and precisely assess the role of CXCL12/CXCR4 signaling. Time-specific lineage tracing demonstrated that endocardial cells differentiated into coronary endothelial cells primarily at mid-gestation. A new mouse line reporting CXCR4 activity—along with cell-specific gene deletions—demonstrated it was specifically required for artery morphogenesis rather than angiogenesis. Integrating scRNA-seq data of endocardial-derived coronary vessels from mid- and late-gestation identified a Bmp2-expressing transitioning population specific to mid-gestation. Bmp2 stimulated endocardial angiogenesis in vitro and in injured neonatal mouse hearts. Our data demonstrate how understanding the molecular mechanisms underlying endocardial angiogenesis can identify new potential therapeutic targets promoting revascularization of the injured heart. [Display omitted] •Endocardium gives rise to coronary vessels primarily at mid-gestation development•Bmp2 stimulates Vegf-A-dependent coronary angiogenesis from endocardium•Bmp2 overexpression reactivates endocardial angiogenesis in injured neonatal heart•Cxcl12/Cxcr4 signaling mediates endocardium-derived artery morphogenesis Identifying how coronary blood vessels develop from their progenitors could inspire therapies promoting revascularization of diseased hearts deprived of blood flow. D’Amato et al. show that Bmp2 stimulates coronary vessel development from endocardial cells in embryonic hearts and that forced Bmp2 expression after birth reactivates endocardial-derived vascularization in injured neonatal hearts.