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DURHAM, N.C. -- Duke University Medical Center researchers have
identified the skeletal muscle changes that occur in response to
endurance exercise and have better defined the role of vascular
endothelial growth factor (VEGF) in creating new blood vessels, a
process known as angiogenesis.

VEGF is a protein known to trigger blood vessel growth by activating numerous genes involved in angiogenesis.

The
researchers' new insights could provide a roadmap for medical
investigators as they seek to use VEGF in treating human conditions
characterized by lack of adequate blood flow, such as coronary artery
disease or peripheral arterial disease.

Using mice as animal
models, the researchers found that exercise initially stimulates the
production of VEGF, which then leads to an increase in the number of
capillaries within a specific muscle fiber type, ultimately leading to
an anaerobic to aerobic change in the muscle fibers supplied by those
vessels. The VEGF gene produces a protein that is known to trigger
blood vessel growth.

The results of the Duke experiments were
presented by cardiologist Richard Waters, M.D., Nov. 8, 2004, at the
American Heart Association's annual scientific sessions in New Orleans.

"It
is known that exercise can improve the symptoms of peripheral arterial
disease in humans and it has been assumed that angiogenesis played a
role in this improvement," Waters said. "However, the clinical
angiogenesis trials to date utilizing VEGF have been marginally
successful and largely disappointing, so we felt it would be better at
this point to return to animal studies in an attempt to better
understand the angiogenic process."

The Duke team performed their
experiments using a mouse model of voluntary exercise. This
experimental approach is important, they explained, because most
skeletal muscle adaptation studies utilize electrical stimulation of
the muscle, which is much less physiologic and does not as closely
mimic what would be expected in human exercise.

When placed in
the dark with a running wheel, mice will instinctively run, the
researchers said. In the Duke experiments, 41 out of 42 mice "ran" up
to seven miles each night. At regular intervals over a 28-day period,
the researchers then performed detailed analysis of capillary growth
and the subsequent changes in muscle fiber type and compared these
findings to sedentary mice.

Mammalian muscle is generally made up
of two different fiber types – slow-twitch fibers requiring oxygen to
function, and the fast-twitch fibers, which function in the absence of
oxygen by breaking down glucose. Because of their need for oxygen,
slow-twitch fibers tend to have a higher density of capillaries.

"Exercise
training is probably the most widely utilized physiological stimulus
for skeletal muscle, but the mechanisms underlying the adaptations
muscle fibers make in response to exercise is not well understood,"
Waters said. "What we have shown in our model is that increases in the
capillary density occur before a significant change from fast-twitch to
slow-twitch fiber type, and furthermore, that changes in levels of the
VEGF protein occur before the increased capillary density."

"Interestingly,
capillary growth appears to occur preferentially among fast-twitch
fibers, and it is these very fibers that likely change to slow-twitch
fibers," Waters said. "Since exercise has the potential to impact an
enormous number of clinical conditions, therapeutic manipulations
intended to alter the response to exercise would benefit from a more
detailed understanding of what actually happens to muscle as a result
of exercise."

The exact relationship between VEGF, exercise
induced angiogenesis, and muscle fiber type adaptation is still not
clear and will become the focus of the group's continuing research. The
findings from the current study, however, are providing important
temporal and spatial clues to the adaptability process.

"Our data
suggests that angiogenesis is one of the key early steps in skeletal
muscle adaptation and may be an essential step in the adaptability
process," Waters continued. "This understanding could be crucial for
designing new studies that can be performed to inhibit the angiogenic
response to exercise in order to directly test the links between
angiogenesis and skeletal muscle plasticity."

The research team was supported by grants from the American Heart Association and the U.S. Department of Veterans Affairs.

Other
members of the Duke team were Ping Li, Brian Annex, M.D., and Zhen Yan,
Ph.D. Svein Rotevatn, Haukeland University Hospital, Bergen, Norway,
was also a member of the team.