Growing Tiny Arteries to Fix Big Heart Problems

The Context: When a major heart artery is blocked, the oxygen-starved areas of the heart are kept healthy by smaller arteries called collateral arteries. Some people have lots of collateral arteries that assist in healing, but others do not.

The Study: A molecule that promotes the growth of collateral arteries after heart injury in mice has been identified in a study at Stanford University led by NYSCF – Robertson Stem Cell Investigator and Associate Professor of Biology Kristy Red-Horse, PhD, and Professor of Cardiothoracic Surgery Joseph Woo, MD. The research appears in Cell.

The Importance: Sparking growth of collateral arteries could give patients a better chance of recovering from heart disease or attack. This study reveals a molecule that could be used as a therapeutic basis for promoting recovery from these conditions, laying the groundwork for future treatments.

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Patients who suffer blockages in major arteries can have very divergent outcomes. While one may lose their life, another may be perfectly fine. What makes the difference?

A major factor in how a patient will recover is the presence of collateral arteries: small arteries that bypass major ones to feed de-oxygenated areas of the heart. Patients with more collateral arteries are more likely to survive heart disease than those without them. Yet it remains unclear how these arteries develop and what factors trigger this process.

New insights into collateral artery development – including a molecule that specifically promotes their growth – have been revealed in a new study published in Cell led by NYSCF – Robertson Stem Cell Investigator and Associate Professor of Biology Kristy Red-Horse, PhD, and Professor of Cardiothoracic Surgery Joseph Woo, MD. This improved understanding of collateral artery development could inform treatments that make up the difference in how patients recover from heart conditions.

The team began by examining newborn mice.

“Neonatal mice have a robust ability to heal injured heart tissue, but they no longer have that ability in adulthood,” Dr. Red-Horse said in a Stanford Medicine news article. “Understanding why could identify ways of reigniting regeneration in adults.”

The researchers found that the newborn mice have this capability because when their heart tissue is damaged, endothelial cells (cells that line the interior surface of blood vessels) migrate along existing capillaries to the site of injury and reassemble to form collateral arteries.

The study found that endothelial cells in newborn mice ‘know’ to do this because of a molecule called CXCL12 found in capillaries around the injured area. When oxygen levels are low, this molecule becomes active and sends out a signal to the epithelial cells to say, “build a collateral artery here.” Remarkably, when the team introduced CXCL12 into adult mice with damaged heart tissue, new collateral arteries formed just as they did in the newborn mice.

The researchers say the next step is to identify other molecules that contribute to collateral artery growth.

“We speculate that there is a whole suite of proteins that support cell migration out of arteries and promotes cell proliferation among the injured cells,” says Dr. Red-Horse.

The team will also investigate whether the mechanism discovered in this study can be therapeutically manipulated to help patients recover more effectively from heart attacks or cardiovascular diseases such as coronary artery disease and atherosclerosis.

Original research article:

Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration

Das S, Goldstone AB, Wang H, Farry J, D’Amato G, Paulsen MJ, Eskandari A, Hironaka CE, Phansalkar R, Sharma B, Rhee S, Shamskhou E, Aualliu D, de Jesus Perez V, Woo JY, Red-Horse K. 2019. Cell.  https://doi.org/10.1016/j.cell.2018.12.023

Learn more about Dr. Red-Horse’s recent research here.