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DURHAM, N.C. – Aging has long been recognized as the worst
risk factor for chronic ailments like atherosclerosis, which
clogs arteries and leads to heart attacks and stroke. Yet, the
mechanism by which aging promotes the clogging of arteries has
remained an enigma.

Scientists at Duke University Medical Center have discovered
that a major problem with aging is an unexpected failure of the
bone marrow to produce progenitor cells that are needed to
repair and rejuvenate arteries exposed to such environmental
risks as smoking or caloric abuse.

The researchers demonstrated that an age-related loss of
particular stem cells that continually repair blood vessel
damage is critical to determining the onset and progression of
atherosclerosis, which 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.

The researchers' novel view of atherosclerosis, 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., they said. Just as importantly, they continued, this
loss of rejuvenating cells could be implicated in a broad range
of age-related disorders, ranging from rheumatoid arthritis to
chronic liver disease.

The results of the Duke research were posted early (July 14,
2003) on the website of the journal Circulation,
(http://circ.ahajournals.org). The study will appear in the
July 29, 2003, issue of the journal.

At issue is the role of stem cells, which are immature cells
produced in the bone marrow that have the potential to mature
into a variety of different cells. The Duke team examined
specific stem cells known as "bone-marrow-derived vascular
progenitor cells" (VPCs).

The researchers believe that it might ultimately be possible
to forestall or even prevent the development of atherosclerosis
by injecting these cells into patients, or to induce the
patient's own stem cells to differentiate into progenitor cells
capable of arterial repair.

"Our studies indicate that the inability of bone marrow to
produce progenitor cells which repair and rejuvenate the lining
of the arteries drives the process of atherosclerosis and the
formation of plaques in the arteries," said Duke cardiologist
Pascal Goldschmidt, M.D., chairman of the Department of
Medicine. "For a long time we've known that aging is an
important risk factor for coronary artery disease, and we've
also known that this disease 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," he 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.
These findings could be the clue to help us explain why
atherosclerosis complications like heart attacks and strokes
are almost exclusively diseases of older people."

Doris Taylor, Ph.D. a senior member of the research team,
sees these findings leading researchers into new areas of
investigation.

"For the first time we are beginning to an insight into how
aging and heart disease fit together -- we've know they go
hand-in-hand – but we haven't understood why," she said.
"Understanding that we either run out of progenitor cells or
that they don't work as well is a big molecular clue to what
might be going on in the whole aging process.

"We are excited that as we unravel the mechanisms of this
process, we will be able to look deeper into heart and vascular
disease, as well as other disease," she added. "These studies
form the basis of future collaborations."

In their experiments, the Duke team used mice specially bred
to develop severe atherosclerosis and high cholesterol levels.
The researchers injected bone marrow cells from normal mice
into these atherosclerosis-prone mice numerous times over 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 bone marrow cells
had significantly fewer lesions in the aorta, despite no
differences in cholesterol levels. Specifically, the
researchers detected a 40-60 percent decrease in the number of
lesions in the aorta, the main artery carrying blood from the
heart.

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

When the researchers examined the vessels under a
microscope, it appeared that the bone marrow cells not only
migrated to where they were needed most, but that they
differentiated into the proper cell types. Some turned into
endothelial cells lining the arteries, while others turned into
the smooth muscle cells beneath the endothelium that help
strengthen the arteries.

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

The researchers also injected these atherosclerotic mice
with donor cells from older mice as well as from younger,
pre-atherosclerotic mice.

"We found that the bone marrow cells from the young mice had
a nearly intact ability to prevent atherosclerosis, while the
cells from the older mice did not," Goldschmidt explained.
"This finding suggests that with aging, cells capable of
preventing atherosclerosis that are normally present in the
bone marrow became deficient in the older mice that had
developed atherosclerosis."

Once the repair cells from the marrow become deficient,
inflammation develops and leads to increase in inflammation
markers (such as CRP). By providing competent bone marrow
cells, the investigators were able to suppress the inflammation
and its blood markers.

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 to restore the integrity of the
circulatory system of patients who already have a lifetime of
atheroslerosis.

"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 of 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."

The research was supported by the National Heart Lung Blood
Institute and the Stanley Sarnoff Endowment for Cardiovascular
Science.

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