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A gene that helps blood vessels feed tumor growth also aids in brain plasticity

Yale Medicine Magazine, 2009 - Winter


A gene that typically helps rogue blood vessels feed tumor growth also appears to play a helpful role in the body—in brain development. Slight genetic variations in the vascular endothelial growth factor (VEGF) gene sequence correlate with changes in the size of the hippocampus, the brain structure involved in memory, emotion and learning. These changes may be linked to a slew of neuropsychiatric disorders including major depression, schizophrenia and dementia.

“There may be subsets of individuals, for example with mood disorder or bipolar disorder, who have hippocampal differences, and they may be the ones who carry these variations in VEGF,” explained Hilary Blumberg, M.D., associate professor of psychiatry, director of the Mood Disorders Research Program and lead author of a paper published online in Biological Psychiatry on August 14.

The researchers used magnetic resonance imaging to determine hippocampus volumes in a group of healthy volunteers who had slight differences in the VEGF gene encoded in their DNA. They then employed statistical analysis to identify any correlation between hippocampus differences and VEGF differences. The study findings suggest that variations in VEGF might contribute to individual differences in hippocampus size and structure.

These findings build on pioneering work conducted by one of the paper’s co-authors, Ronald S. Duman, Ph.D., Elizabeth Mears and House Jameson Professor of Psychiatry, professor of pharmacology and director of the Division of Molecular Psychiatry and Abraham Ribicoff Research Facilities. Duman recently explored VEGF function in the brain and found that it helped new nerve cells grow, specifically in the hippocampus.

Playing a part in neurogenesis is an unconventional role for VEGF. The gene is known to help cancers grow by laying down new networks of blood vessels that feed malignant cells. Blocking VEGF function is a main goal in the treatment of breast, lung and colorectal cancers, among others.

Joel E. Gelernter, M.D., professor of psychiatry and director of the Division of Human Genetics in Psychiatry, who was examining genetic variations in VEGF, joined Blumberg and Duman for a collaborative effort.

“We’re trying to understand at a basic level of cell signaling how disruptions or alterations could contribute to the function of the hippocampus and circuits within the hippocampus, and how these disruptions influence behavior and illness,” said Duman. Toward that end, Gelernter offered up his genetic expertise, Duman contributed knowledge about the molecular role of VEGF in the brain from his animal studies and Blumberg brought her brain imaging know-how to bear.

The findings of the current study complement another recent discovery from the research trio. They found that, compared to healthy subjects, adults with bipolar disorder had significantly smaller hippocampus volumes, which were linked to variations in the brain-derived neurotrophic growth factor (BDNF) gene (published online on August 13 in Neuropsychopharmacology). Duman predicts that VEGF may behave similarly, in that VEGF variations may make individuals either more or less vulnerable to stress-related mood disorders.

To follow up on this prediction, Blumberg and co-lead author Fei Wang, M.D., Ph.D., plan to study VEGF genetic variations in individuals with mood disorders to understand how these gene changes may influence both brain structure and behavior. Ultimately, identifying genetic variants that predispose individuals to mood disorders could pave the way to patient screening for early disease detection and possibly smarter treatments.