Tracing the origins of de novo coronary collateral formation in cardiac repair.

Coronary collateral arteries have been proposed to form de novo through artery reassembly, a process in which arterial endothelial cells (ECs) migrate away from preexisting arteries and reassemble into new arteries. Using genetic tools that trace arterial ECs, we found that their contribution to collaterals is modest. Dual genetic lineage tracing revealed that capillary ECs, rather than arterial ECs, serve as the major building blocks for de novo collaterals. The capillary-to-collateral conversion is functionally crucial for cardiac repair. In addition, transient Vegfa expression through modified messenger RNA markedly promoted collateral formation. Mechanistically, vascular endothelial growth factor (VEGF) drives arterialization by regulating HES1 transcription through YY1/SETD1A-mediated H3K4 trimethylation. Collectively, these findings redefine the cellular origin and mechanism of coronary collateral formation and highlight its role in facilitating efficient cardiac repair.