Protein important to nerve development serves the dual purpose of stimulating the growth of blood vessels

Nov 1 2004

A protein important to nerve development serves the dual purpose of stimulating the growth of blood vessels, researchers from the University of Utah School of Medicine and Stanford University have discovered.

The discovery opens the possibility that blood vessel growth (angiogenesis) one day may be induced, or stymied, for therapeutic use against heart disease, cancer, and other illnesses, according to Dean Y. Li, M.D., Ph.D., associate professor of internal medicine in the U of U School of Medicine's Division of Cardiology. Li is corresponding author of an article that details the findings to be published next week in the Proceedings of the National Academy of Sciences online.

The study focuses on Netrin-1, part of the netrin family of proteins, one of four major classes of neural guidance "cues" that induce axons, or nerve fibers, to extend in specific directions during development. Recent evidence has indicated that the other three classes of neural guidance cues--ephrins, semaphorins, and slits--function as angiogenic regulators. But until now, netrins had not been shown to have a part in blood vessel formation.

Nerves and blood vessels often follow parallel paths of development, which suggests that common cues may induce both processes. In tissue cultures and animal models, Li and the other researchers showed that Netrin-1 "stimulates proliferation, induces migration, and promotes adhesion of endothelial cells and vascular smooth muscle cells."

"It makes sense that factors that guide nerves also guide blood vessel growth," Li said. "This work indicates that there is an expanding number of signals that regulate vessel growth or angiogenesis. Identifying these signals and their interaction are critical steps required for manipulating, blocking, or stimulating blood vessel growth for therapeutic purposes."

The researchers' data demonstrate that Netrin-1 is a neural guidance cue with the "unique ability to attract both blood vessels as well as axons, and is capable of functioning as a vascular growth factor," they write.

Understanding what factors induce blood vessel growth could have important implications for treating disease in the future.

Tumors, for example, depend on blood vessels to supply critical nutrients to grow. If blood vessel growth in tumors could be stopped, it may help fight cancer.

Conversely, inducing blood vessel growth may help people with ischemic heart disease whose hearts don't get enough blood.

Although the discovery about Netrin-1 shows promise, therapeutic starting or stopping of blood vessel growth to cure human disease is at least 15 years away--if it proves viable, Li said.

Li began studying whether Netrin-1 promotes blood vessel growth after discovering a vascular receptor for another neural guidance factor. Next, he wants to look at the roles of other netrins in blood vessel development and identify the receptors required for the vascular effects of Netrins.

Along with Li, other researchers on the project included Kye Won Park, Dana Crouse, Satyajit Karnik, and Lise K. Sorensen, the U of U School of Medicine's Program in Human Molecular Biology and Genetics; Kelly J. Murphy, U of U Department of Cardiology; Mark Lee and Calvin J. Kuo, Stanford University School of Medicine.