In a study published in Science, a team led by Prof. ZHOU Bin from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, along with Prof. LIU Kathy O. from The Chinese University of Hong Kong, developed a series of genetic lineage-tracing tools to investigate the origins of newly formed coronary collateral arteries after myocardial infarction, and revealed that de novo coronary collateral arteries arise predominantly from capillary endothelial cells rather than pre-existing arterial endothelial cells.

For coronary artery disease, when coronary artery blocks, insufficient blood supply results in myocardial ischemia and infarction. Clinical interventions can restore blood flow, but are invasive and may cause complications. Collateral artery formation has been attributed to the expansion and remodeling of pre-existing arteries. However, a growing number of studies show that new collateral arteries can develop in regions lacking pre-existing arteries, raising a question of their cellular origin.

Studies have suggested that collateral arteries form through an "artery reassembly" process. This conclusion is mainly based on the Cx40-CreER lineage-tracing system, which may also label a subset of capillary endothelial cells with arterialization potential. Besides, newly formed collateral arteries can acquire Cx40 expression after injury and may therefore be directly labeled due to residual tamoxifen activity, complicating the interpretation of lineage tracing results.

In this study, the researchers developed multiple genetic lineage-tracing tools including dual recombinase-based systems and a synNotch-based genetic recording system that identifies endothelial cells associated with mature arterial structures. They found that only a limited fraction of newly formed collateral arteries originated from pre-existing arterial endothelial cells and the majority were derived from capillary endothelial cells. Selective genetic ablation of capillary-derived arteries increased myocardial fibrosis and enlarged infarct areas, demonstrating that these vessels are essential for restoring blood perfusion and promoting cardiac repair after injury.

Moreover, the researchers demonstrated that capillary-to-artery transition also occurred in adult hearts after myocardial infarction. Through the investigation of the molecular mechanisms, they found that the transient activation of VEGF-A by using modified mRNA promoted the formation of functional collateral arteries and improved cardiac repair, while sustained VEGF signaling failed to promote the generation of fully functional mature arteries.

Mechanistically, the researchers showed that VEGF-A induced higher endothelial expression of the transcription factor YY1, which recruited the histone methyltransferase SETD1A to enhance H3K4me3 at Hes1 regulatory regions. This epigenetic regulation activated HES1, a key Notch pathway effector, thereby driving capillary endothelial cells toward an arterial fate.

This study reveals a regulatory pathway that drives capillary-to-artery transition. It provides a new understanding of the coronary collateral artery formation after cardiac injury, and new insights into vascular regeneration and potential therapeutic strategies for ischemic heart disease.