NEW YORK (Feb. 25, 2005) -- Physician-scientists at Weill Cornell Medical College have made the surprising finding that a protein called BDNF (brain-derived neurotrophic factor), which is usually considered important only for cells in the nervous system, actually plays a critical role in the growth and maintenance of blood vessels. This research, to be published in the March 1 online edition of Journal of Clinical Investigation (JCI), may lead to new treatments for vascular disease and cancer.

Cancer and vascular disease, the two leading killers of Americans under 85, are in some ways mirror images of one another. One way that tumors grow is by hijacking the body's blood supply system, making new arteries and blood vessels for themselves in a process called "angiogenesis." And, in several forms of heart disease, the blood supply to the heart is inadequate, and the heart needs to generate new blood vessels.

The traditional responses by doctors to these heart diseases have been invasive catheter-based and open-heart surgeries. As an alternative, cardiologists are seeking to find ways to use drugs to grow new arteries and blood vessels, thus avoiding these invasive procedures, along with the painful period of healing they require. A similar drug treatment is sought by physicians treating patients with peripheral vascular disease, in which the blood supply to the legs is compromised.

Doctors who treat cancer also are interested in angiogenesis, only from the opposite point of view -- they seek ways to prevent tumors from getting an adequate blood supply, thus starving them to death.

Most attention on angiogenesis has focused on regulating a protein called vascular endothelial growth factor (VEGF), commonly thought to be the body's chief blood-vessel-growing agent.

Proving the adage that it is easier to destroy than to build, work to create cancer drugs that block VEGF has progressed quickly, with at least two cancer-starving drugs already on the market. Yet companies have struggled to develop drugs that can promote angiogenesis and feed the heart. The initial approach to promote angiogenesis has been to administer VEGF directly to the heart, either as a gene or a protein. While this approach may lead to the formation of new vessels, the vessels can be leaky and disorganized.

In 1999, a research team led by Dr. Barbara Hempstead, Co-Chief of Weill Cornell Medical College's Division of Hematology-Oncology and the senior author of the current paper, discovered that mice lacking the gene for BDNF were not viable -- they died around the time of birth. While the blood vessels in their hearts began to form and develop normally, at a certain point they just fell apart and the mice died. "It became clear that VEGF may kick off the angiogenic process, but that BDNF may be required to stabilize and maintain the vasculature," says Dr. Hempstead, who is also The O. Wayne Isom Professor of Medicine at Weill Cornell and Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"We see that with levels of gene expression as well," adds Dr. Hempstead. "VEGF starts out being expressed at a high level during development and tapers off in adulthood, while BDNF starts out low, rises, and remains elevated in the adult."

In the JCI paper, Dr. Hempstead teamed with a large group of Weill Cornell Medical College researchers -- including first co-author Dr. Pouneh Kermani, a postdoctoral fellow in hematology-oncology; Dr. Ronald Crystal, Chair of the Department of Genetic Medicine; and Dr. Shahin Rafii, Director of the Ansary Center for Stem Cell Therapeutics -- to explore the more difficult question of the role played by BDNF in adult angiogenesis -- again using mice as a model for humans. They found that administration of BDNF either via gene therapy or in protein form was as powerful as VEGF in promoting angiogenesis, and that the new vasculature was well organized. They hypothesized that local, chronic delivery of low doses of BDNF may be the most effective therapeutic approach.

Most astonishingly, they found that the BDNF had profound effects on "hematopoietic stem cells" -- immature cells that reside in the bone marrow, and leave the bone marrow to form new blood cells, blood vessels, and other tissues. Working both on cells and on living mice, they found that BDNF caused the stem cells to leave the bone marrow at a higher rate than normal, and to home to areas of ischemia, or insufficient blood supply.

"We found that BDNF was able to stimulate the hematopoietic stem cells as much as VEGF did," said Dr. Kermani.

"This means that BDNF may stimulate angiogenesis not only by causing existing blood vessels to sprout, but by mobilizing and attracting stem cells to the site of need, where they implant and mature. Absolutely amazing!" exclaimed Dr. Rafii, a VEGF and stem-cell expert, and contributing author.

This research provides the foundation for further work to explore the role of BDNF in therapeutic angiogenesis. If those experiments are successful and a pharma or biotech partner is found, clinical trials in humans could follow.

Since angiogenesis is fundamental to both cardiovascular disease and cancer (not enough angiogenesis in vascular disease; too much in cancer), one would expect there to be a role for BDNF in cancer as well -- albeit a pathological one. Dr. Hempstead, together with Dr. Roger Pearse, another Weill Cornell researcher in the Division of Hematology-Oncology, recently published a paper in Blood entitled, "A Neurotrophin Axis in Myeloma: TrkB and BDNF Promote Tumor Cell Survival." This paper demonstrates that in myeloma, a devastating cancer in which a subset of blood cells proliferates and crowds out healthy blood cells, the cancerous cells are able to use BDNF signaling to promote their own survival.

Brain-derived neurotrophic factor (BDNF) was first identified 23 years ago. It gets the first part of its name, "brain-derived," from the place where it was first found -- the brain. The second part of its name -- "neurotrophic factor" -- comes from the Greek, "neuro" for nerve and "troph" for nourish. At first, the name was apt, but as this recent work shows, BDNF plays a much larger role than its name implies.

The other authors on the JCI paper -- all from Weill Cornell Medical College -- are Dahlia Rafii, David K. Jin, Paul Whitlock, Wendy Schaffer, Anne Chiang, Loic Vincent, Matthias Friedrich, Koji Shido, and Neil R. Hackett. The research was supported by the Burroughs Wellcome Fund (Dr. Hempstead) and by the National Heart, Lung, and Blood Institute (Drs. Hempstead, Rafii, and Crystal).

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