Could this be important for treating heart disease?

Yes, we hope that understanding collaterals might be key to a new type of regenerative therapy. What we’ve been looking at is how this type of blood vessel develops and whether, at some point in the future, inducing them to grow might be an effective therapy for people with blocked coronary arteries.

Heart attacks occur when the blood can’t go around a vascular blockage. Like strokes, they happen in the blood vessels. When the heart muscle is denied oxygen and nutrients, heart tissue dies. That’s why, in many instances, heart failure ensues. But what if we could find a way to generate new coronary arteries to bring nutrients to the heart? Might we prevent heart muscle death?

One of our big discoveries is that collaterals in the mammalian heart form easily just after birth — that is, in neonates, or newborns. This may be one reason why, in the rare cases of newborns having heart attacks, they can heal quickly. Their collaterals extend out of regular arteries and migrate toward an injury. But in adults, the process is less efficient.

How far have you gotten in your research?

Well, among things we’ve discovered is that these collateral arteries are made from the same types of cells as regular arteries.

Prior to our research, it was thought that new collaterals were only transformed capillaries — small, preexisting blood vessels that were being expanded and remodeled. That does happen, but collaterals can in fact also grow out anew from existing arteries.

In experiments with young mice, we created blood vessel blockages and heart attacks. That set off the development of new collaterals in the animals. The collaterals originated in the lining of regular arteries and then grew to where the damage occurred.

Later, we identified a protein, CXCL12, that activates collateral artery formation. We used it to reawaken the process in adult mice. Right now, we are searching for other proteins involved in this process. We next intend to learn why some humans have collaterals and others don’t.

Prominent scientists say that you and your colleagues have transformed coronary research. Your Stanford colleague Irving Weissman, the legendary stem cell researcher, told me, “Kristy has given us an entirely different way to look at blood vessels.”

I think he’s speaking of my postdoctoral work with Mark Krasnow. Till we published it in 2010, the conventional wisdom was that the coronary arteries were made from the cellular covering of the embryonic heart — tissue called the epicardium. In our experiments, though, we saw that they instead originate from two other sources: a vein beside the heart called the sinus venosus and the inner lining of the heart, the endocardium.

To discover this, I used new techniques for looking at heart development. The old way to get a window on what was happening was to make tissue sections, very thin slices of tissue that looked at little pieces of the heart one at a time. I brought in this idea to look at the entire organ at once. This approach revealed the origins of the coronary arteries because you could see where they were emerging from, and you could see physical connections that you couldn’t when you just sliced and diced tissue.

Moreover, Irv Weissman had created this novel technique for looking at individual cells. He’d made this lineage of specially modified mice in which we could label just a few cells in an area with a color. After marking the cells, you could see during development where the cells and their offspring migrated to. We used that to help us confirm that the coronary arteries came from a vein and the inner lining of the heart.

It must have been exciting to discover something so unexpected.

Absolutely. It was thrilling when we actually saw that there were these two different progenitors of the coronaries and we saw them come from the inside of the heart chamber.

You could see the inside of the heart kind of spit out these little balls. They popped out in these circles, as if they were tiny beach balls. And then they spread out. I was like, “What? Wow!” It was not how we anticipated blood vessels growing.

What’s also fascinating is that if you look at the individual cells early in the development of the coronaries, you can tell which ones came from the vein and which ones came from the heart lining. They carry different molecular signatures. But by the time the coronaries have matured, the cells all seem to converge on the exact same form, down to the level of identical gene expression. So they respond to cardiac injuries in the same way.

Why would nature have two different ways of making the same cells? That seems oddly wasteful.

There are at least a couple of ideas about that. One possibility is that because coronary arteries are so vital to an animal’s health, this gives us a backup way to grow them. In experiments, we’ve shown that if the growth of coronary vessels from the sinus venosus is interrupted, the vessels from the endocardium expand to fill the gap.

Having two sources may also help the network of coronary arteries grow faster. More starting material means faster expansion. The optimum growth of the vessels seems to be important for making sure that the heart muscle itself develops quickly into a tight, compact form, which the heart needs to beat efficiently.