Researchers identify gene linked to development of a critical coronary artery

Most people have right-dominant hearts—which to a doctor or a researcher means they have an artery that extends from the right side of their hearts to supply oxygenated blood to the back side. For some people, this artery, called the posterior descending artery, comes from the left side or from both directions. A study has found that the gene CXCL12 is connected to this artery’s formation and that its directional pattern is set very early in human development.

The findings, reported in the journal Cell, represent a step toward developing “medical revascularization,” a long-term goal of Stanford researchers to create a treatment for blocked or limited-flow arteries by growing new ones to compensate. 

“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.” 

Several coronary arteries deliver blood and oxygen to the human heart: The two main arteries are on the front of the heart on the right and left sides. To supply oxygenated blood to the back of the heart, the posterior descending artery branches off from one of those main arteries. For an estimated 80% of humans, that artery comes from the right main coronary artery, but for about 10%, it comes from the left. In another 10%, there are two of these arteries of roughly equal size that branch off the right and left main arteries and extend to the back of the heart.

To better understand what determines this arterial patterning, Red-Horse collaborated with co-senior author Tim Assimes, associate professor of cardiovascular medicine in the Stanford School of Medicine.

Assimes, who also treats patients at the Palo Alto VA Medical Center, saw an opportunity in the large medical data set from the Department of Veterans Affairs’ Million Veteran Program. It contains information of more than 60,000 veterans who have undergone angiograms, a medical imaging procedure to detect possible artery blockages. This data includes whether their hearts had right-, left- or co-dominant arteries on the back as well as genetic samples. 

The researchers conducted genetic analysis and found ten locations within the human DNA code tied to the development of the artery on the back of the heart—the strongest of which was CXCL12. Previous work from Red-Horse’s group had already shown that mice who received a dose of the protein associated with the gene CXCL12 grew new arterial branches in their damaged heart tissue, so the latest finding in humans indicates that the gene and its protein play a critical role in human artery formation as well. 

“We now have evidence that this patterning of our two major coronary arteries is controlled by difference in our DNA code we inherit from our parents, and the top signal is near a gene that is also responsible for the growth and development of coronary arteries,” Assimes said.

After finding this connection, the researchers imaged fetal hearts and found that CXCL12 was expressed at the time the directional dominance of the posterior descending artery was established. Further experiments with mice also showed that reducing the protein produced by CXCL12 caused those mice to develop left- or co-dominant patterns. 

Whether having the more common right-dominant artery pattern ultimately confers more or fewer protections against heart disease is not yet known. 

Yet, the discovery of the gene that potentially controls this branching opens up the possibility of discovering ways to make new collateral arterial branches, meaning purposefully growing additional arteries that could still deliver oxygen to the heart when another artery is blocked. Currently, treatments to relieve limited or blocked arteries are invasive and mechanical, such as open-heart bypass surgery and the placement of artificial stents. 

Next the researchers plan to investigate the DNA variants that cause differences in expression of CXCL12 and work on designing ways to target the gene activation toward the creation of a therapeutic treatment.

Acknowledgments:

Red-Horse is a member of Stanford’s Bio-X and Institute for Stem Cell Biology and Regenerative Medicine. Assimes is a member of Stanford’s Wu Tsai Human Performance Alliance. Both are members of Stanford’s Cardiovascular Institute and Maternal & Child Health Research Institute.

Additional Stanford collaborators on this study include co-senior author Shoa Clarke, assistant professor in the School of Medicine, and four co-first authors: former postdoctoral scholar Pamela E. Rios Coronado and research scientist Xiaochen Fan, both in biology (H&S), as well as current and former postdoctoral scholars from the School of Medicine, Jiayan Zhou and Daniela Zanetti, respectively. Other co-authors from biology include former research technician Pratima Prabala and doctoral students Jeffrey A. Naftaly and Azalia M. Martínez Jaimes. Additional co-authors from the School of Medicine include doctoral student Salil S. Deshpande, staff scientist Ivy Evergreen, postdoctoral scholar Pik Fang Kho, Professor Virginia D. Winn, Professor Philip S. Tsao, Associate Professor Anshul Kundaje, and Assistant Professor Anca M. Pasca. Stanford computer science doctoral student Soumya Kundu is also a co-author on this study. 

This work also includes co-authors who are affiliated with the National Research Council in Cagliari, Italy; University of California, San Diego; University of Pennsylvania Perelman School of Medicine; Sarnoff Cardiovascular Research Foundation; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; VA Boston Health Care System; Corporal Michael J. Crescenz VA Medical Center, Philadelphia; Rocky Mountain Regional VA Medical Center; VHA Office of Quality and Patient Safety; University of Colorado School of Medicine; Howard Hughes Medical Institute; and VA Million Veteran Program.

This research received support from the VA, National Institutes of Health, Howard Hughes Medical Institute, Doris Duke Foundation, Perelman School of Medicine at University of Pennsylvania, and a gift from the Smilow family.