CU Medicine and the Chinese Academy of Sciences (CAS) have, for the first time, identified the cellular origin and formation mechanism of newly developed collateral arteries in the damaged heart using a revolutionary genetic lineage-tracing technology. The study unveils that capillaries across the heart muscle “upgrade” into collateral arteries, essentially constructing natural emergency bypasses within the heart that restore blood flow to ischaemic regions.

(From left) Mr Hou Yangfeng, a PhD student from the Department of Chemical Pathology at CU Medicine; Professor Kathy Lui Oi-lanof the Department of Chemical Pathology at CU Medicine; and Professor Zhou Bin, from the Centre for Excellence in Molecular Cell Science, Chinese Academy of Sciences.

A research team led by The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) and the Chinese Academy of Sciences (CAS)-CUHK Joint Laboratory for Cardiovascular Sciences has, for the first time, identified the cellular origin and formation mechanism of newly developed collateral arteries in the damaged heart.

Published in the premier academic journal Science, the study overturns the long-held belief that new arteries arise from pre-existing arteries, opening a new avenue for treating ischaemic heart disease. It shows that when coronary arteries are blocked, capillaries across the heart muscle “upgrade” into collateral arteries, essentially constructing natural emergency bypasses within the heart that restore blood flow to ischaemic regions.

Novel genetic lineage-tracing technology unlocks the mystery of collateral artery formation

Coronary artery disease remains the most common heart disease in Hong Kong and the leading cause of death worldwide, accounting for over half of all heart disease-related fatalities locally. The heart beats continuously throughout life, relying on coronary arteries to deliver oxygen and nutrients. When a coronary artery is blocked, downstream heart muscle is deprived of blood and may become damaged or die. In severe cases, this can lead to myocardial infarction (heart attack). While standard treatments like balloon angioplasty or open-heart bypass surgery are widely used, they carry inherent limitations and risks, particularly for patients with severe, diffuse blockages involving multiple blood vessels.

Nevertheless, some individuals possess a natural “backup system”. When a main coronary artery becomes obstructed, collateral arteries can bypass the blockages and restore blood flow. However, the origin of these lifesaving bridges has long remained a mystery in cardiovascular research.

To solve how the heart might repair itself, Professor Zhou Bin’s team from the CAS-CUHK Joint Laboratory for Cardiovascular Sciences developed a revolutionary genetic lineage-tracing technology, a “cell-contact history recorder”, that can permanently label mature arterial endothelial cells, without relying on traditional markers and inducers. They also established a highly precise tracking system that specifically identifies the process by which capillaries convert into arteries, while effectively suppressing background signals from unchanged capillaries. The technology is comparable to illuminating only those roads undergoing expansion on a nighttime map, allowing researchers to observe the vascular “upgrade” process with precision.

Using this platform, the researchers discovered that when main coronary “highways” are blocked, ordinarily inconspicuous capillaries, the “narrow alleyways”, rapidly initiate an upgrade and remodelling programme. The capillaries progressively widen and strengthen, ultimately forming collateral arteries with an arterial structure and blood-supplying function. These newly formed vessels bypass blockages to connect major blood vessels and restore the delivery of blood and nutrients to ischaemic heart muscle.

VEGFA-YY1 signalling axis—the master conductor of vascular upgrading

To uncover how the “alley-to-highway” transformation occurs, Professor Zhou’s team partnered with Professor Kathy Lui Oi-lan and her team at CU Medicine. They identified vascular endothelial growth factor A, or VEGFA, as the master driver of this process. Mouse studies showed that temporarily increasing VEGFA levels in the injured hearts markedly increased capillary-to-artery conversion, shrinking ischemic areas and improving heart function. Yet excessive VEGFA produced an overgrowth of immature, poorly functional arterial-like vessels, akin to “shoddy construction”.

Mr Hou Yangfeng, a PhD student from the Department of Chemical Pathology at CU Medicine who participated in the research, said: “To achieve transient yet highly efficient delivery, our team employed an mRNA therapeutic approach to supply VEGFA to the heart and promote repair. Mechanistically, VEGFA activates the key downstream transcription factor YY1, which guides capillaries to transform into functional arteries. This defines a molecular regulator for vascular network remodelling and pinpoints a tractable therapeutic target.”

Ushering in a new era of cardiovascular therapy

Professor Zhou Bin, the corresponding author, from the Centre for Excellence in Molecular Cell Science, Chinese Academy of Sciences, commented: “Current treatment for severe coronary artery disease commonly include percutaneous coronary intervention with stent placement (commonly known as “balloon angioplasty”) and open-heart coronary artery bypass surgery (commonly known as “bridging surgery”). However, they may have limitations or pose risks for patients with diffuse coronary artery disease involving multiple blockages. This work reshapes our understanding of the heart's intrinsic repair capacity and offers concrete hope for patients with ischaemic heart disease – the leading cause of death worldwide.”

Professor Kathy Lui Oi-lan, who co-led the study from the Department of Chemical Pathology at CU Medicine, remarked: “Looking ahead, the goal is to precisely tune the VEGFA-YY1 signalling pathway to unlock endogenous repair and promote the reliable formation of collateral circulation. The team is currently conducting clinical research on this pathway-guided, tissue-targeted modulation, with the aim of providing a gentler, safer treatment strategy for all patients with ischaemic heart disease.”

Professor Kathy Lui says that this study found that modulating the VEGFA-YY1 signaling pathway may unlock endogenous repair and promote the reliable formation of collateral circulation. The team hopes to carry out clinical studies in the Greater Bay Area as the next step to confirm the efficacy of developing related therapeutics.

Professor Zhou states that over approximately seven years, the team developed a novel genetic lineage tracing technique that effectively tracks the formation of collateral arteries, uncovering the mystery behind the origin of these “bridges of life.” This study further discovered that VEGFA can promote the natural migration of cells, which is believed to offer safer new therapies for patients in the future.