New study adds hope that method used to address coronary artery blockage in mice might also work in humans

By Christopher Vaughan

May 23, 2025

The blockage of coronary arteries that supply oxygen to the heart can lead to a heart attack, and potentially the death of heart tissue. The solution has long been cardiac bypass surgery—sewing in a new artery that shunts blood around the blockage. This requires open heart surgery, a major surgery that can be hard on patients, however.

For years, institute member Kristy Red-Horse, PhD and her colleagues have envisioned another solution: a drug that prompts the heart to grow new arteries to bypass coronary blockages and feed the oxygen-starved heart muscle.

“We know that the fetus will grow what we call collateral arteries in the developing heart, but they are small and likely regress after birth,” Red-Horse says. “Theoretically, what we hope to do is be able to reactivate the genetic programs that allowed these arteries to grow early in development so that adult heart patients can benefit.”

A few years ago, the Red-Horse lab was able to show that a protein called CXCL12 would promote the growth of collateral arteries in mice. This work was done with Stanford Professor Joseph Woo, MD, who is the Norman E. Shumway Professor of Cardiovascular Surgery at Stanford. If the researchers injected CXCL12 into a mouse with myocardial infarction—where blood supply is cut off or severely diminished to one area—collateral arteries would grow to the infarcted area. The question remained, however, whether CXCL12 would also do the same thing in humans.

Now, Red-Horse and her colleagues have begun to answer that question. In the April issue of the journal Cell, the investigators show that CXCL12 is a key modifier of coronary artery development in humans, and have found genetic variants that affect the expression of CXCL12. This work was done in association with Stanford Associate Professor of Medicine Themistocles (Tim) Assimes, MD, PhD.  “Now we have strong evidence that what we have seen in mice is happening in humans,” Red-Horse said.

The key to making this discovery turned out to be a natural variation in the organization of the artery that supplies blood to the back of the heart. Eighty percent of the population is what cardiologists call “right dominant” because the artery that feeds the back of the heart branches off from the right coronary artery. But 10 percent of the population are “left dominant” because that area of the heart is fed by blood ultimately coming from the left coronary artery. In the remaining 10 percent of the population who are co-dominant, arterial blood supply to the back of the heart comes from both left and right coronary arteries.

If these variations are being driven genetically, they offer researchers the opportunity to see if CXCL12 is involved in human arterial formation in the heart. “We wanted to take advantage of this tremendous experiment that nature has performed,” Red-Horse said.

Using anonymized medical records from over 60,000 cardiology patients in VA hospitals, they were able to do a genome-wide association study (GWAS) of the patients with right, left and co-dominant development of their coronary arteries. Using that information, the researchers looked for genes that seemed to be key drivers of these variations. They found ten spots in the genome where genetic activity had significant associations with particular variations in cardiac arterial dominance.

“We found that genetic variants in some of these ten spots were near genes known to play a role in cardiac development, but the most statistically significant spot, the one with the greatest effect, was right by the CXCL12 gene,” Red-Horse said. The researchers think the variations in this gene affect the how and when CXCL12 is made during development, which affects the left, right or mixed dominance pattern that develops. “Everything about the domain that we identified is consistent with a gene that helps guide these developing arteries to where they need to go.”

In further work, the investigators found more evidence that CXCL12 regulates human arterial development and patterning, creating hope that the kinds of collateral artery growth they are able to induce in mice can be reproduced in humans.

Red Horse said that the next steps will be to understand which genes regulate the creation of CXCL12, and find those that will work as targets for future drug development.

“If we can create a medicine to induce the growth of collateral arteries in human, we might create a medical alternative to open heart surgery, and perhaps even allow people to be treated early, before severe symptoms show up,” Red-Horse said.