2026-08-26 中国科学院（CAS）
＜関連情報＞
- https://english.cas.cn/newsroom/research-news/202608/t20260821_1188664.shtml
- https://www.science.org/doi/10.1126/science.ady3027
心臓修復における新規冠状動脈側副血行路形成の起源をたどる Tracing the origins of de novo coronary collateral formation in cardiac repair
Mingjun Zhang, Maoying Han, Yangfeng Hou, Zixin Liu, […] , and Bin Zhou
Science Published:20 Aug 2026
DOI:https://doi.org/10.1126/science.ady3027
Structured Abstract
INTRODUCTION
Coronary artery disease remains a leading cause of death worldwide. Acute occlusion of a coronary artery deprives downstream myocardium of oxygen and nutrients, precipitating myocardial infarction (MI). Coronary collateral arteries, which serve as natural bypass conduits between preexisting coronary artery branches, can restore perfusion to ischemic tissue and improve clinical outcomes. However, the cellular origin and molecular regulation of de novo collateral artery formation remain incompletely defined. Conventional lineage tracing has been constrained by imperfect marker specificity and the temporally variable nature of tamoxifen-dependent labeling.
RATIONALE
To delineate the cellular origin of coronary collaterals, we engineered complementary genetic lineage–tracing systems. These include intersectional strategies that reduce false-positive labeling and a cell-cell contact-triggered system that permanently marks mature arterial endothelial cells (ECs) without tamoxifen. We also developed tools to label capillary-derived and artery-derived vessels simultaneously within the same animal, enabling direct comparison of distinct EC sources after MI, and we interrogated the signaling pathways that govern this process.
RESULTS
We identified a subset of capillary ECs that express the arterial marker Cx40, highlighting specificity limitations of conventional tracing. Across multiple independent systems, including intersectional genetics and a synthetic Notch-based method, we found that mature arterial ECs contribute modestly to new collaterals after MI. Concurrent tracing within single hearts revealed that capillary ECs constitute the primary building blocks of collateral arteries in both neonatal and adult mice, with a modest contribution from preexisting arterial ECs. Selective ablation of capillary-derived collaterals impaired repair, increased fibrosis, and worsened cardiac function, establishing their functional necessity. To enhance collateralization, we modulated vascular endothelial growth factor (VEGF) signaling. Sustained pathway activation expanded immature arterial-like ECs but failed to improve repair. By contrast, transient delivery of Vegfa by using modified mRNA promoted functional collaterals, improved perfusion, reduced scarring, and enhanced cardiac function after injury. Mechanistically, VEGF-A activated the transcription factor YY1 (yin yang 1), which recruited the chromatin regulator SETD1A to promote histone H3 lysine 4 trimethylation (H3K4me3) and induce the arterial regulator HES1 (hairy and enhancer of split–1), orchestrating capillary-to-artery conversion.
CONCLUSION
De novo coronary collaterals formed after MI arise primarily through arterialization of capillaries, with a modest contribution from preexisting arteries. We define a VEGF-A–YY1-SETD1A–HES1 epigenetic axis that orchestrates this process and demonstrate that transient VEGF stimulation can boost functional collateral formation and improve cardiac repair. These results position capillary arterialization as a central mechanism of endogenous revascularization and present a potential therapeutic strategy for ischemic heart disease.
Cellular origins of coronary collateral arteries.
Whole-mount imaging and schematic of neonatal mouse hearts under non-MI and MI (myocardial infarction) conditions. After injury, de novo coronary collaterals (purple arrowheads) form predominantly from capillary ECs (green) and modestly from preexisting arterial ECs (red).
Abstract
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.
