A
team of U.Va. researchers has developed a complex computer
model that can accurately predict how and where new blood
vessels will form in response to two different stimuli:
changes in blood pressure and the delivery of a growth protein.
Their results — believed to be the first in the emerging
field of systems biology — hold promise for future
developments in the treatment of chronic heart disease and
diabetes through angiogenesis, or the growth of new blood
vessels. The results also could be used in the development
of treatments for cancer that involve shutting off the blood
supply to cancerous tissue.
Their method — using a complex, quantitative, predictive
model — also has the potential to speed up the development
of new medical treatments and should be of interest to the
pharmaceutical and medical-device industries.
“Large pharmaceutical companies are investing heavily
in computational systems biology, and our study indicates
they are on the right track,” said Thomas C. Skalak,
professor of biomedical engineering and principal investigator.
“Quantitative biology holds the key to the medical
discoveries of the future.”
The U.Va. team’s findings will be released Feb. 6
in the online edition of FASEB Journal, published for the
Federation of American Societies for Experimental Biology,
at www.faseb.org. An illustration of their work will appear
on the cover of the journal’s print edition in April.
“To our knowledge, this is the first time that a computer
model of a complex biological system has accurately predicted
how a network of new blood vessels will grow in response
to specific stimuli,” Skalak said. “Experimental
observation verified our in silico results.”
Skalak, past president of the Biomedical Engineering Society,
and U.Va. research scientists Shayn M. Peirce and Eric J.
Van Giesen conducted the computational bioengineering research
and co-authored the FASEB Journal article.
The U.Va. researchers set out to answer two questions:
1) How are blood vessels assembled on a cell-by-cell basis
in mammals? and 2) How do the responses of individual cells
to environmental stress or injury affect the construction
of single blood vessels and networks of blood vessels? Their
goal was to better understand how a living, multicellular
system grows and adapts to various stimuli and, ultimately,
to be able to engineer vascular tissue systems by harnessing
natural mechanisms.
The research team built on the work of Hungarian-born mathematician
John Louis von Neumann, borrowing his “Cellular Automaton”
theory, and used Uri Wilensky’s NetLogo simulation
software, developed at Northwestern University’s Center
for Connected Learning and Computer-Based Modeling, to build
a complex computer model that mimics blood-vessel growth
in mammals.
They also drew on 50 rules of cellular behavior published
by other researchers for elements of their model. But no
one had pulled all the pieces together in the same way to
answer those questions.
The U.Va. researchers created a complex, “multicellular
simulation” in mammalian tissue, integrating data from
thousands of individual cells, including the endothelial
cells and smooth-muscle cells needed to build the blood-vessel
walls. Among the 50 factors the model considers for each
cell as it interacts with other cells are varied rates of
cellular growth and cellular migration in space and over
time. The model also takes into account the dynamic environment
of the surrounding tissue, which influences the pace and
direction of blood-vessel construction.
The researchers’ model predicted that an increase
in blood pressure would stimulate cells to build blood vessels
with a larger diameter, increasing the delivery of oxygen
through an expanded blood flow; and that the delivery of
a growth protein would stimulate cells to build longer blood
vessels, extending the reach of the blood flow through an
expanded network of blood vessels.
This research into microvascular remodeling has multiple
applications in the fields of tissue engineering, developmental
biology and reparative medicine, according to Skalak. In
particular, the results may contribute to the development
of processes to help the body heal itself after heart disease
or traumatic injury, or help with the creation of in vitro
systems to grow new tissue to replace that lost to injury
or disease.
In addition, the U.Va. team is investigating the impact
of other stimuli on blood vessel growth, on vascular cells
and on matrix proteins, which are involved in cellular and
tissue cohesion.
The U.Va. research is funded in part by the National Institutes
of Health and by the Whitaker Foundation, a private, nonprofit
foundation based in Rosslyn, which is dedicated to improving
human health through support for biomedical engineering.
