By repairing vessels, bone marrow cells slow atherosclerosis in mice

November 19, 2002

CHICAGO -- Duke University Medical Center researchers have shown that an age-related loss of specific stem cells that continually repair damage to blood vessels is critical to determining the onset and progression of atherosclerosis. Stem cells are immature cells that have the potential to mature into a variety of different cells.

This novel view of the disease, based on experiments in mice, constitutes a potential new avenue in the treatment of one of the leading causes of death and illness in the U.S., the researchers said.

It could ultimately be possible, they continued, to inject these stem cells into patients, or to induce the patient's own stem cells to differentiate into progenitor cells capable of arterial repair, to forestall or even prevent the development of atherosclerosis, a disease process that causes arteries to clog and become less elastic. When atherosclerosis affects arteries supplying the heart with oxygen and nutrients, it causes coronary artery disease and puts patients at a much higher risk for a heart attack.

"We believe that the arteries of young people are remarkably resistant to damage because stem cells known as vascular progenitor cells (VPCs) produced in the bone marrow are continually repairing damage caused to the vessels," said Frederick Rauscher, a fourth-year medical student at the Duke University School of Medicine who presented the results of the Duke today (Nov. 19, 2002) at the 75th annual scientific session of the American Heart Association.

"As we age, it appears that we exhaust or deplete our store of VPCs, which means that damage to vessels cannot be repaired," Rauscher continued. "This idea that stem cells can rejuvenate vessels could explain one of the biggest questions in our understanding of atherosclerosis -- why does it appear to be a disorder seen almost exclusively in older people?"

Rauscher's presentation is one of five finalists for the Louis N. and Arnold M. Katz Basic Research Prize for Young Investigators.

Arteries can be damaged over time by the collective effects of high cholesterol, high blood pressure, diabetes, smoking and even infection. The researchers believe that VPCs can help offset these risk factors by rejuvenating the vessels.

"These findings are very important," said Pascal Goldschmidt, M.D., senior member of the research team and chief of cardiology at Duke. "For a long time we've known that aging is an important risk factor for coronary artery disease, and we've also known that these diseases can be triggered by smoking, bad diet, diabetes, high blood pressure and other factors.

"But if you compare someone who is over 60 with someone who is 20 with the same risk factors, there is obviously something else going on as well," Goldschmidt continued. "The possibility that stem cells may be involved is a completely new piece of the puzzle that had not been anticipated or appreciated before."

In their experiments, the Duke team used mice specially bred to develop severe atherosclerosis and high cholesterol levels. The researchers injected VPCs from normal mice into these atherosclerosis-prone mice numerous times during a 14-week period. As a control, an equal of number of the same kind of atherosclerosis-prone mice went untreated.

"After 14 weeks, the mice treated with the stem cells had a significantly reduced number of lesions in the aorta, despite no differences in cholesterol levels," Rauscher said.

Specifically, the researchers detected a 69 percent decrease in the number of lesions in the aorta, the main artery of the heart, and a 42 percent decrease in lesions where the aorta meets the heart.

Using specific staining techniques on the aortas, the researchers were able to determine that the donor stem cells "homed in" on areas where atherosclerotic lesions are most common, especially where smaller vessels branch off from larger vessels. These areas tend to experience "turbulence" or "eddying" of blood.

"We then looked at the vessels under a microscope, it appeared that the stem cells not only went where they were needed most, but that they differentiated into the proper cell types," Rauscher said. "Some turned into endothelial cells lining the artery, while others turned into the smooth muscle cells beneath the endothelium that help move blood through the arteries."

To further prove that the donor stem cells were responsible for rejuvenating arteries, the scientists measured the lengths of structures at the end of chromosomes known as telomeres of the endothelial cells and found that they were longer in the treated mice than the untreated mice. Over time, telomeres are known to shorten as the organism ages.

"These experiments support the new concept that the loss of a suitable source of VPCs contributes to the development of atherosclerosis," Rauscher said. "Whereas traditionally we have focused on removing multiple sources of vascular injury, we now demonstrate that an alternative approach, vascular rejuvenation, can positively impact the development of atherosclerosis in the continued presence of vascular injury."

While the direct use of stem cells as a treatment may be many years off, the researchers said, it is likely that strategies currently used to reduce the risks for heart disease -- such as lifestyle modifications and/or different medications -- preserve the collection of these rejuvenating stem cells for a longer period of time, which delays the onset of atherosclerosis.

For Goldschmidt, a major question is whether researchers can somehow use these cells for patients who already have a lifetime of atherosclerosis.

"We need to look at the possibility of re-training stem cells that would otherwise be targeted to a different organ system to help repair the cardiovascular system," he said. "Another interesting question is whether rheumatoid arthritis, as an example for chronic inflammatory disorders, causes stem cell loss, since such arthritis is a risk factor for coronary artery disease. The chronic process of joint disease could consume stem cells that could otherwise be used for the repair of the cardiovascular system. We are just beginning to appreciate the links between stem cells and cardiovascular disease."
Rauscher is supported by a fellowship from the Stanley Sarnoff Endowment for Cardiovascular Science.

Other members of the Duke team include: Bryce Davis, Priya Ramaswami, Anne Pippen, David Gregg, Brian Annex, M.D., Chunming Dong, M.D., Tao Wang, Ph.D., and Doris Taylor, Ph.D.

Duke University Medical Center

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