The work also offers the first proof that nature has site-specific growth signals that could one day be exploited to treat a variety of diseases in which blood vessels -- or the need for new ones -- play important roles, such as in cancer, heart disease and stroke.
In their laboratory experiments, the research team discovered that two proteins linked to congenital blindness normally interact and signal blood vessels in the developing eye to branch into capillaries. The faulty versions found in people, however, don't interact correctly, preventing capillaries from forming and leading to either of two blinding diseases.
"Clearly, if you want to encourage blood vessel growth in a particular place, or stop it in a particular place, you'd have to use a specific signal or control production of a widely recognized signal only where and when it is needed," says Jeremy Nathans, M.D., Ph.D., a Howard Hughes Medical Institute investigator and a professor of molecular biology and genetics in Hopkins' Institute for Basic Biomedical Sciences.
"This work shows that nature actually has built specialized systems to control blood vessel growth in tiny areas. With time, it may be possible to start and stop blood vessel growth better than we can right now, hopefully improving the treatment of retinal disease," he adds.
Currently, the best-known blood vessel growth signal, VEGF, or vascular endothelial growth factor, is being tested as a treatment for peripheral vascular disease in the legs and to restore blood flow to damaged heart muscle. But giving such a powerful general growth signal, recognized throughout the body, risks triggering unwanted blood vessel growth, perhaps feeding undetected tumors.
By contrast, the growth signal the Hopkins team identified seems to function only in the developing retina, where it promotes capillary formation, and in the inner ear, where it appears to help maintain the capillary network. It isn't known yet whether the signal is used later in life.
"Growth of blood vessels, like growth of nerves, must be precisely controlled, given the almost identical vascular anatomy from individual to individual," says Nathans. "What we learn about blood vessel growth in the eye may point to likely control systems in other kinds of cells."
Postdoctoral fellow Yanshu Wang, Ph.D., co-first author of the report, started the investigation by examining changes in mice missing Frizzled-4, which is defective in one form of familial exudative vitreoretinopathy, or FEVR (pronounced "fever"). She found that the mice had remarkably similar blood vessel problems in the eye and ear as seen in an earlier study of mice missing Norrin, which is faulty in Norrie [sic] disease. Both diseases are characterized by problems in blood vessel development in the retina; people with Norrie disease also go deaf over time.
Because of the similarities Wang found, co-first author and postdoctoral fellow Quiang Xu, Ph.D., examined whether the Norrin and Frizzled-4 proteins interact. He found that the two proteins bound each other selectively and strongly, and that Norrin caused efficient activation of the Frizzled-4 signaling pathway.
"The Norrie disease gene was found almost 12 years ago, but until now no one had been able to figure out what its product protein did or how it caused the disease," says Nathans. "Because the proteins behind the Norrie disease and FEVR are parts of the same process, these aren't two diseases, they are really two versions of the same disease."
The scientists also examined the effects of some of the disease-causing mutations in the Norrie gene and in Frizzled-4. Xu discovered that the proteins from these mutated genes can't interact properly, squelching the signal.
The team now plans structural and biochemical studies to pinpoint exactly how Norrin binds to and turns on Frizzled-4, and experiments to find other players in the Frizzled-4-Norrin pathway.
While stopping blood vessel growth might help make cancer a chronic, rather than deadly, disease, treating conditions such as heart disease, peripheral vascular disease and stroke may be helped by encouraging blood vessel growth to make up for blocked or poorly functioning vessels.
The research was funded by the Howard Hughes Medical Institute, the National Institutes of Health, the National Eye Institute, the Ruth and Milton Steinbach Fund, and the Ronald McDonald House Charities Fund.
Authors on the paper are Xu, Wang, Nathans, Philip Smallwood and John Williams of Johns Hopkins; Alain Dabdoub, Chad Woods and Matthew Kelley of the National Institute on Deafness and Other Communication Disorders; Li Jiang and Kang Zhang of the University of Utah; and William Tasman of Wills Eye Hospital, Philadelphia, Pa.
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