Coronary “natural mechanism” paves way for new therapeutic option for IHD

Researchers from the Chinese University of Hong Kong (CUHK) and the Chinese Academy of Sciences (CAS)–CUHK Joint Laboratory for Cardiovascular Sciences have discovered that de novo coronary collaterals formed after myocardial infarction (MI) arise primarily through arterialization of capillaries, with only a modest contribution from pre-existing arteries, challenging the long-held belief that new arteries arise from pre-existing arteries.

The need for strategies that promote collateral artery formation to restore blood flow to ischaemic myocardium and improve recovery of damaged heart tissue led the team to develop complementary genetic-tracing systems to delineate the cellular origin of coronary collaterals.  These systems included intersectional strategies that reduce false-positive labelling and a cell-cell contact-triggered system that permanently marks mature arterial endothelial cells (ECs) without tamoxifen (Tam). The team 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 interrogated the signalling pathways that govern this process. [Science 2026;393:eady3027]

According to the prevailing model prior to this study, in patients who lack sufficient pre-existing arterial shunts that enlarge in response to coronary obstruction, arterial ECs migrate out, proliferate, and reassemble into collateral arteries to restore blood flow endogenously, independent of pre-existing shunts. This “artery reassembly” model is supported by lineage-tracing studies which use the Tam-inducible Cx40-CreER tool. However, this conventional lineage tracing is constrained by imperfect marker specificity and the temporally variable nature of Tam-dependent labelling, often producing false-positive labelling. [Cardiovasc Res 2016;109:419-430; Cell 2019;176:1128-1142; J Mol Cell Cardiol 2022;165:158-171; Arterioschler Thromb Vasc Biol 2023;43:1455-1477; PLoS One 2012;7:e33529]

The current study identified a subset of capillary ECs expressing the arterial marker Cx40, highlighting specificity limitations of conventional tracing. Across multiple independent systems, including intersectional genetics and a synthetic Notch-based method, mature arterial ECs were found to contribute only 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 pre-existing arterial ECs. Selective ablation of capillary-derived collaterals impaired repair, increased fibrosis, and worsened cardiac function, establishing their functional necessity.

 “To achieve transient yet highly efficient delivery, our team employed an mRNA therapeutic approach to supply vascular endothelial growth factor [VEGF]-A to the heart and promote repair,” elaborated Mr Yangfeng Hou, a PhD student and member of the research team. “Mechanistically, VEGF-A activates the key downstream transcription factor ying yang 1 [YY1], which guides capillaries to transform into functional arteries. This defines a molecular regulator for vascular network remodelling and pinpoints a tractable therapeutic target.”

“Current treatment for severe coronary artery disease [CAD] commonly includes percutaneous coronary intervention with stent placement [balloon angioplasty] and open-heart coronary artery bypass surgery [bridging surgery]. However, they may have limitations or pose risks for patients with diffuse CAD involving multiple blockages,” said leader of the study, Professor Bin Zhou, from the Centre for Excellence in Molecular Cell Science, Chinese Academy of Sciences. “This work reshapes our understanding of the heart's intrinsic repair capacity and offers concrete hope for patients with ischaemic heart disease [IHD].”