Researchers find reason why many vein grafts fail

NIH intramural-led study uncovers biology behind improper graft remodeling, points to treatment strategies

National Institutes of Health researchers have identified a
biological pathway that contributes to the high rate of vein graft
failure following bypass surgery. Using mouse models of bypass surgery,
they showed that excess signaling via the Transforming Growth Factor
Beta (TGF-Beta) family causes the inner walls of the vein become too
thick, slowing down or sometimes even blocking the blood flow that the
graft was intended to restore. Inhibition of the TGF-B signaling
pathway reduced overgrowth in the grafted veins.

The team, led by Manfred Boehm, M.D., chief of the
Laboratory of Cardiovascular Regenerative Medicine at NIH's National
Heart, Lung, and Blood Institute, identified similar properties in
samples of clogged human vein grafts, suggesting that select drugs
might be used in reducing vein graft failure in humans.

Endothelial cells not only form the
inner lining of a blood vessel, but also contribute to blood vessel
narrowing as shown in this mouse vein graft model. Endothelial cells
(green) lose their typical morphology and become more like smooth muscle
cells (red). This change in cellular properties indicates that
endothelial-to-mesenchymal transition (EndMT) is operative in vein graft
stenosis.

This study will be published March 12 in Science Translational Medicine.

Bypass surgery to restore blood flow hindered by clogged
arteries is a common procedure in the United States. The great
saphenous vein, which is the large vein running up the length of the
leg, often is used as the bypass conduit due to its size and the ease
of removing a small segment. After grafting, the implanted vein remodels
to become more arterial, as veins have thinner walls than arteries and
can handle less blood pressure. However, the remodeling can go awry
and the vein can become too thick, resulting in a recurrence of clogged
blood flow. About 40 percent of vein grafts experience such a failure
within 18 months of the operation.

Boehm and his colleagues examined veins from mouse
models of bypass surgery, and discovered that a process known as an
endothelial-to-mesenchymal transition, or EndoMT, causes the inside of
the vein to over-thicken. During EndoMT, many of the endothelial cells
that line the inner surface of the vein proliferate and convert into
more fibrous and muscle-like cells. These mesenchymal cells begin to
accumulate on the inner wall, narrowing the vessel.

This process was triggered by TGF-Beta, a secreted
protein that controls the proliferation and maturation of a host of
cell types; the researchers found that TGF-Beta becomes highly
expressed just a few hours after graft surgery, indicating the
remodeling starts fairly quickly.

Boehm’s team also looked at human veins taken from failed
bypass operations, and found corroborating evidence for a role for
EndoMT in human graft failure. In short term grafts (less than one
year), many of the cells inside the human veins displayed both
endothelial and mesenchymal cell characteristics, while in long-term
grafts (more than six years) the cells on the inner wall were primarily
mesenchymal in nature.

“This study shows for the first time that endothelial
cells in the vein directly contribute to blood vessel narrowing
following a vein graft,” Boehm said. “Now that we better understand the
mechanism that causes the abnormal thickening, we can look for
therapeutic strategies to attenuate it, and reduce the number bypass
reoperations we need to perform each year.”

Boehm cited the high-blood pressure drug Losartan, which
can inhibit TGF-Beta, as one possible treatment strategy, though more
proof of concept studies are needed before any clinical studies can
commence.

In addition to Dr. Boehm’s lab at NHLBI, other
contributors to this study included the Medical College of Wisconsin,
Milwaukee; Barts and the London NHS Trust, London, UK; Cairo
University, Egypt; University of Glasgow, Scotland, UK; Tubingen
University, Germany; CVPath Institute Inc., Gaithersburg, Md., and the
Mount Sinai School of Medicine, New York City.

To schedule an interview with Dr. Boehm, contact the NHLBI Office of Communications at 301-496-4236 or NHLBI_news@nhlbi.nih.gov.

Part of the National Institutes of Health, the National Heart, Lung,
and Blood Institute (NHLBI) plans, conducts, and supports research
related to the causes, prevention, diagnosis, and treatment of heart,
blood vessel, lung, and blood diseases; and sleep disorders. The
Institute also administers national health education campaigns on women
and heart disease, healthy weight for children, and other topics.
NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.

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