Watching Blood Vessels Grow and Shrink
2-D simulation shows angiogenesis as it happens
Microscopic capillaries grow on demand, snaking toward hungry cells needing their blood supply. Understanding how to control this process could help scientists promote wound healing or halt cancer in its path. A new computer model simulates how a key molecule (VEGF, or vascular endothelial growth factor) summons vessels to sprout: It spills out of a hungry cell and travels toward a vessel, with increased concentrations in areas with few vessels. The two-dimensional model also predicts the actual number of VEGF molecules at that edge, another novel advance.
”There have been over 10,000 papers published on VEGF and not one shows a molecular-level computation,” says Aleksander Popel, PhD, professor of biomedical engineering at the Johns Hopkins University School of Medicine. The work appeared in the September 2006 issue of PLoS Computational Biology.
VEGF promotes the growth of blood vessels, a process known as angiogenesis. Developing treatments to halt or promote angiogenesis is rife with complex issues: Too much VEGF can lead not only to cancer but also to abnormal blood vessel growth. And VEGF concentration is not the only issue; to control vessel growth one needs to control the VEGF gradient across the tissue—a challenging task. Previous computational models have addressed this question in vitro. But this model takes that work a step further, modeling VEGF gradients in a complex in vivo environment.
Feilim Mac Gabhann, PhD, now a postdoctoral fellow at the University of Virginia, built the model from electron micrographs and in vitro data on the size and shape of vessels, muscle cells, and the organic matrix between them. He simulated different scenarios to analyze how VEGF moved between muscle and vessel. He found that VEGF concentrations increased dramatically when the model mimicked oxygen-starved muscle. In addition, the model predicted a 12 percent change in VEGF concentration over 10 microns—a characteristic no other research had attempted to quantify. This gradient may be significant for capillary sprouting, the researchers suggest.
“This research is right on the edge,” says Dan Beard, PhD, professor of physiology at Medical College of Wisconsin. “They are just at the point where they’ve put everything together. They are ready for applications where there is potential for big payoffs.” But Beard warns they need to prove the model truly mimics in vivo angiogenesis—a task the team admits will be difficult.
Mac Gabhann and Popel next want to mimic drug activity to watch molecules interacting with VEGF. If a drug can reduce VEGF to a trickle instead of a flow so that vessels don’t grow, it might help fight cancer. If a drug increases VEGF diffusion, or guides blood vessel formation more precisely, it might help with wound healing. “We can model the behavior of therapeutics that you just can’t do in vivo,” Mac Gabhann says.