(PHILADELPHIA) – How do blood
clots maintain that precise balance of stiffness for wound healing
and flexibility to go with the flow? Researchers at the University
of Pennsylvania School of Medicine and the School
of Arts and Sciences have shown that a well-known protein structure
acts as a molecular spring, explaining one way that clots may stretch
and bend under such physical stresses as blood flow. They report
their findings in a Letter in the latest online edition of the Biophysical
Journal. This knowledge will inform researchers about clot
physiology in such conditions as wound healing, stroke,
are a three-dimensional network of fibers, made up primarily of
the blood protein fibrinogen,
which is converted to fibrin
during clotting. A blood clot needs to have the right degree of
stiffness and plasticity to stem the flow of blood when tissue is
damaged, yet be flexible enough so that it does not block blood
flow and cause heart
attacks and strokes.
In previous research, senior author John
W. Weisel, PhD, Professor of Cell
and Developmental Biology, measured the elastic properties of
individual fibers and found that the fibers, which are long and
very thin, bend much more easily than they stretch, suggesting that
clots deform in flowing blood or under other stresses, primarily
by the bending of their fibers.
The current research extends those earlier findings to the molecular
level, suggesting a way that individual fibers flex - by the unraveling
of the three, tightly twisted rod-like regions within fibrinogen
molecules, called alpha-helical
coiled-coils. The researchers measured this change by pulling engineered
strands of fibrinogen molecules using an atomic
force microscope. This alpha-helical coiled-coil “spring”
is a common motif in protein structure, first identified more than
50 years ago and so its stretchiness may have broader implications
in biology and medicine.
By understanding mechanical processes at the molecular level, it
may eventually be possible to see how they relate to the mechanical
properties of single fibers and a whole clot. This knowledge may
enable researchers to make predictions about the function of differently
formed fibrin clots in the circulating blood or in a wound. For
example, when clots are not stiff enough, problems with bleeding
arise, and when clots are too stiff, there may be problems with
which results when clots block the flow of blood. First author André
Brown, a physics graduate student at Penn,
notes that this research is a first step towards understanding the
mechanics of the relationship between clot elasticity and disease.
Recent research by other scientists showed that a fibrin fiber could
stretch four to five times its original length before snapping.
"This is among the most extensible, or stretchy, of polymers
that anyone has ever found," says Weisel. "But, how is
the stretching happening at a molecular level? We think part of
it has to be the unfolding of certain parts of the fibrin molecule,
otherwise how can it stretch so much?"
Previous research from senior coauthor Dennis
Discher, PhD, Professor in the Physics
& Molecular Biology graduate groups, suggested the possibility
that alpha-helical structures in some blood-cell proteins unfold
at low levels of mechanical force. But "it wasn't known before
that the coiled coil region of the fibrinogen molecule would be
the part to unfold under the stress induced by the atomic force
microscope," notes Brown.
Once the origins of the mechanical properties of clots are well
understood, it may be possible to modulate those properties, note
the study authors. "If we can change a certain parameter perhaps
we can make a clot that's more or less stiff," explains Weisel.
For example, various peptides
or proteins, such as antibodies,
bind specifically to fibrin, affecting clot structure. The idea
would be to use such compounds in people to alter the properties
of the clot, so it can be less obstructive and more easily dissolved.
In the future, the researchers will examine other processes at the
molecular and fiber levels that may be responsible for the mechanical
properties of clots to eventually develop a model that can then
be used to predict the effect of changes at one scale on clot properties
at other scales. Such a model should be useful for developing prophylactic
and therapeutic treatments for many aspects of cardiovascular disease
and stroke, suggest the investigators.
I. Litvinov is also from Penn. This research was funded by the
of Health and the Natural
Sciences and Engineering Research Council of Canada.
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