Coronary artery disease remains a leading cause of mortality and disability worldwide. Following coronary artery blockage, insufficient blood supply results in myocardial ischemia and infarction. Although clinical interventions such as coronary stent implantation and coronary artery bypass surgery can restore blood flow, these approaches are invasive and may cause complications. Therefore, understanding how the heart activates its endogenous vascular regenerative capacity to restore perfusion remains an important goal in cardiovascular research.
Coronary collateral arteries function as a natural bypass system that supplies blood to ischemic regions and are associated with improved clinical outcomes. Traditionally, collateral artery formation has been attributed to the expansion and remodeling of pre-existing arteries, a process known as arteriogenesis. However, new collateral arteries can also develop in regions lacking pre-existing arteries, raising a fundamental question regarding their cellular origin.
In a study published in Science, a research team led by Professor ZHOU Bin from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences, in collaboration with Professor LIU Kathy O. from The Chinese University of Hong Kong, developed a series of advanced genetic lineage-tracing tools to investigate the origins of newly formed coronary collateral arteries after myocardial infarction. The researchers discovered that de novo coronary collateral arteries arise predominantly from capillary endothelial cells rather than pre-existing arterial endothelial cells. The study further revealed a VEGF-A–YY1–SETD1A–H3K4me3–HES1 regulatory pathway that drives capillary-to-artery transition, providing new insights into vascular regeneration and cardiac repair.
Previous studies suggested that collateral arteries form through an “artery reassembly” process, in which pre-existing arterial endothelial cells migrate, proliferate, and reassemble into new collateral arteries. However, these conclusions were mainly based on the Cx40-CreER lineage-tracing system, which may also label a subset of capillary endothelial cells with arterialization potential. In addition, 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.
To overcome these limitations, the researchers established multiple high-precision lineage-tracing strategies, including dual recombinase-based systems and a synNotch-based genetic recording system that identifies endothelial cells associated with mature arterial structures.
Using these approaches, the researchers found that only a limited fraction of newly formed collateral arteries originated from pre-existing arterial endothelial cells, whereas 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.
The researchers further demonstrated that capillary-to-artery transition also occurs in adult hearts after myocardial infarction. Investigating the molecular mechanisms, the team found that transient activation of VEGF-A using modified mRNA (modRNA) promoted the formation of functional collateral arteries and improved cardiac repair, whereas sustained VEGF signaling failed to promote the generation of fully functional mature arteries.
Mechanistically, 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.
Together, this study provides a new understanding of coronary collateral artery formation after cardiac injury. By combining innovative lineage-tracing technologies with molecular and functional analyses, the researchers demonstrate that capillary endothelial cells serve as the predominant cellular source of de novo collateral arteries and uncover the epigenetic mechanism controlling endothelial arterialization. These findings provide new insights into vascular regeneration and potential therapeutic strategies for ischemic heart disease.
Reference: https://doi.org/10.1126/science.ady3027
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