Team designs computer model to predict pathways of blood vessels
Model may have applications for treatment of heart disease, diabetes and cancer

By Charlotte Crystal

Photo by Andrew Shurtleff

Thomas Skalak, professor and chairman of biomedical engineering (left), and research associate Shayn Peirce are two members of the U.Va. research team that developed a complex computer model for accurately predicting how and where new blood vessels will form. Their findings were published Feb. 6 in FASEB, the journal of the Federation of American Societies for Experimental Biology.

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.