Scientists at Vanderbilt University Medical Center have cracked an important step in the code that cells destined to form blood vessels use to recognize and connect to one another.
The findings by researchers in the Vanderbilt Cancer Center and the Vanderbilt Center for Vascular Biology could have implications for treatment of the nation's two leading causes of death, heart disease and cancer. The findings also may contribute to a better understanding of how an embryo's circulatory system develops.
In the early formation of blood vessels, endothelial cells (which line large blood vessels and form the capillaries) are stimulated to grow and migrate until they hook up with each other and meet an existing blood vessel to which they connect.
Dr. Thomas O. Daniel, Catherine McLaughlin Hakim Professor of Medicine, likens the process to someone driving a car down a street looking for a specific address. The driver reads the addresses one by one, recognizes the targeted address and stops the car.
"Our work focuses on the molecules that direct endothelial cells to appropriate cell partners and permit endothelial cells to 'know they've arrived'," explained Daniel, who heads the Center for Vascular Biology as well as the Cancer Center's Host-Tumor Interaction Research Program.
"That kind of targeting function is necessary for vascular development and for angiogenesis (development of new blood vessels) to support tumors or to repair damaged heart muscle."
Writing in the April 15 issue of the European Molecular Biology Organization (EMBO) Journal, Daniel, his research fellow Dr. Uyen Huynh-Do and their colleagues report a molecular link between an endothelial receptor called EphB1 and the machinery that mediates cell attachment, integrin alpha 5 beta 3, which had earlier been implicated in angiogenesis.
These Vanderbilt researchers proposed in an earlier report in the journal Genes and Development that EphB1 is an important, if not dominant, player in endothelial cell-cell recognition and that it directs cell attachment behavior of endothelial cells. Previous work by researcher David Cheresh at the Scripps Research Institute demonstrated that angiogenesis is disrupted by agents that block alpha 5 beta 3 connects with the extracellular matrix. The matrix can be likened to "the mortar between the bricks" that holds cells together.
"This system appears to work something like the street addresses we use to target our destinations," Daniel said. "Vascular endothelial cells appear to use EphB1 to identify their correct partners by reading the density of its binding partner as 'addresses' on cells they contact."
The researchers went on to show that alpha 5 beta 3 functions like the "brakes" when EphB1 reads the correct "address." Daniel noted that drug therapies that block the connection of alpha 5 beta 3 with matrix are already being studied in early clinical trials in cancer patients. The goal of such "anti-angiogenesis" therapies is to block the formation of the new blood vessels that tumors need to grow and spread.
"We think this paper is very important because it links this cell-to-cell recognition machinery to something that was first shown to play importantly into angiogenesis and which has already moved into the clinical setting for more investigation," Daniel said.
Recent work from the California Institute of Technology has shown Eph receptors and their binding partners are required for development of the early embryonic circulation.
The new findings may ultimately contribute to the development of more targeted treatments -- with fewer side effects -- for cancer or other diseases that involve angiogenesis, Daniel said. For instance, a highly specific therapy might block the development of vessels supporting a specific tumor but not affect wound healing. Or a drug might be developed specifically to promote the growth of new blood vessels to restore blood flow to the heart after a coronary artery becomes blocked.
"The family of Eph receptors and binding partners is very large, and specific members are expressed at regional sites in the vascular system," Daniel said. "It is likely that blood vessels supporting tumors express a small subset of these 'address recognition machines.' Molecular antagonists that might block only one but not the whole class of receptors should offer very high specificity and avoid potentially serious complications that would occur if all angiogenesis were blocked."
Other collaborators were Elke Stein, Ph.D., former graduate student at Vanderbilt who is now at the University of California-San Francisco; Andy A. Lane, M.D., Ph.D., a former Vanderbilt undergraduate now at Washington University; research associate Hua Liu; and Douglas Paul Cerretti, a collaborator from Immunex Corp. in Seattle, which provided the antibody.
The work was supported by the National Institutes of Health, the National Cancer Institute, the T.J. Martell Foundation and the Swiss Science Foundation.