Gene Discovery Could Help Grow New Heart Arteries

To supply oxygenated blood to the back of the heart, the posterior descending artery branches off from one of the main arteries. In approximately 80% of individuals, this artery originates from the right main coronary artery, while about 10% of people have it branching from the left main artery. In another 10%, two arteries of similar size branch off from the right and left main arteries, extending to the back of the heart. A new study has identified a gene that may influence the early development of this crucial artery, potentially leading to methods of growing new arteries to bypass blockages and treat heart disease.

The study, led by researchers at Stanford University (Stanford, CA, USA), discovered that the gene CXCL12 is linked to the formation of the posterior descending artery and that its pattern is established early in human development. Published in the journal Cell, the findings represent a significant step toward developing "medical revascularization"—a long-term goal of the researchers to create treatments for blocked or restricted arteries by growing new ones to restore blood flow. To explore what influences this arterial patterning, the team analyzed a large medical dataset from the Department of Veterans Affairs’ Million Veteran Program, which includes data from over 60,000 veterans who have undergone angiograms to detect potential artery blockages. This dataset also provided information about the dominance of the artery (right, left, or co-dominant) and included genetic samples.

The researchers performed genetic analyses and identified ten regions in the human genome associated with the development of the posterior descending artery, with CXCL12 emerging as the most significant. Previous research had already demonstrated that when mice were given a dose of the CXCL12-associated protein, new arterial branches formed in the damaged heart tissue. This new finding in humans suggests that CXCL12 and its protein are crucial for human artery formation. The team then examined fetal hearts and found that CXCL12 was expressed at the time when the directional dominance of the posterior descending artery is established. Further experiments in mice revealed that reducing the protein produced by CXCL12 led to the development of left-dominant or co-dominant artery patterns.

It remains unclear whether having the more common right-dominant artery pattern provides more protection against heart disease. However, the identification of the gene responsible for this branching process opens new possibilities for growing collateral arteries—additional arteries that could deliver oxygen to the heart if another artery is blocked. Currently, treatments for blocked or narrowed arteries are invasive and mechanical, such as open-heart bypass surgery and the use of artificial stents. Moving forward, the researchers plan to investigate the DNA variants that influence CXCL12 expression and explore methods to activate the gene in order to develop therapeutic treatments.

“For the first time, we have evidence of a gene that regulates the development of one of the most important types of arteries in the human body,” said Kristy Red-Horse, co-senior author of the study and biology professor in the Stanford School of Humanities and Sciences. “And if we know the development pathways of these important arteries, then we can perhaps regrow them by reintroducing these pathways in a diseased heart.”