Capillaries can regenerate coronary collateral arteries, study finds

A group of Chinese researchers recently revealed that capillary vessels could give rise to coronary collateral arteries, which are expected to serve as a natural bypass system and inspire a gentler and more effective new treatment for ischemic heart disease.

The findings were published in the journal Science on Friday. The study was conducted by a research team led by Zhou Bin from the Center for Excellence in Molecular Cell Science at Chinese Academy of Sciences, in collaboration with Kathy Lui from the Chinese University of Hong Kong.

Coronary artery disease remains a leading cause of mortality and disability worldwide. Following coronary artery blockage, insufficient blood supply usually 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.

On the other hand, coronary collateral arteries, which are naturally possessed in some lucky people's hearts, can function as a natural bypass system. They can supply blood to ischemic regions and can generally generate better clinical outcomes.

The researchers compared the entire vascular network to a transportation system, where arteries are like wide highways and capillaries are like narrow, intricate paths. They discovered that when a highway is interrupted, these narrow paths rapidly initiate an "upgrade and renovation project", continuously widening and strengthening themselves to acquire the structure and function of arteries. Eventually, they develop into new "highways" connecting the two main arteries, restoring the supply of blood and nutrients to the damaged heart muscle.

Researchers have been making efforts for long to find the origins of de novo coronary collateral arteries. Traditionally, collateral artery formation has been attributed to the migration and reassembly of preexisting arteries. But traditional genetic models have some limitation, raising a fundamental question regarding the real cellular origin of collateral arteries.

To address the question, the research team developed a series of advanced genetic lineage-tracing tools to trace arterial endothelial cells and capillary endothelial cells, and investigate the origins of newly formed coronary collateral arteries after myocardial infarction.

The team disclosed that they established multiple high-precision lineage-tracing strategies, including their globally acclaimed dual recombinase-based systems, and a synNotch-based genetic recording system that precisely identifies endothelial cells associated with mature arterial structures.

With these approaches, they discovered that de novo coronary collateral arteries arise predominantly from capillary endothelial cells, with a modest contribution of preexisting arterial endothelial cells. It offers a new understanding of coronary collateral artery formation after cardiac injury, and such capillary-to-collateral conversion is seen to be functionally crucial for cardiac repair.

The researchers also found that transient activation of vascular endothelial growth factor A using modified mRNA can promote the formation of functional collateral arteries and improved cardiac repair. Based on the discovery, the study further revealed a regulatory pathway that drives capillary-to-artery transition, providing fresh insights into vascular regeneration and potential therapeutic strategies for ischemic heart disease.

"We see the findings as very meaningful. For those who were not luckily born with coronary collateral arteries, we could potentially use the capillaries to regenerate the arteries. Moreover, the solid approaches used in the study, especially the dual recombinase-based system, can effectively work out in other researches as well, such as lung and liver repair and regeneration. Over 1,000 labs across the globe are using it in various fields, and we hope the system can benefit a wider world in the future," said Zhou.