© 2003 by Oxford University Press
© 2003 Oxford University Press
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VEGF’s Surprise Role in Neurodegenerative Disease
Researchers have long considered VEGF to be a major player in the development and growth of cancer, but now a new role for the growth factor has emerged: as a player in diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, a fatal condition involving the body’s motor neurons. ALS usually affects individuals after age 40 or 50, causing weakness, paralysis, and death.
"The role of hypoxia in the upregulation of VEGF, its vascular effects, and its feedback loop in angiogenesis and cancer is well known," said Peter Carmeliet, M.D., Ph.D., an angiogenesis researcher at the Flanders Interuniversity Institute for Biotechnology in Leuven, Belgium. "But its role in the susceptibility to the neurodegenerative disease of ALS is new."
In a retrospective study of more than 1,900 Swedish, British, and Belgian patients, Carmeliet found three "at risk" genetic variations or haplotypes that gave individuals a 1.8 times greater risk of ALS. People in the "at risk" variation group had lower circulating VEGF levels and reduced VEGF gene transcription. Moreover, mice with a similar genetic type of low VEGF levels were "unusually susceptible to persistent paralysis after spinal cord ischemia. But treatment with VEGF protected these type of mice from ischemic motor neuron death," Carmeliet said.
"VEGF levels in normal humans are quite variable," said Carmeliet. "And for example, we know that in people with sleep apnea, their levels are quite high, correlating to a relative lack of oxygen," he said. "To get an idea of what is normal for individuals, one must be followed over time to develop an idea of what is normal for them."
In cancer as well as neurology, VEGF and perfusion are linked: if blood vessels are not working properly, there may be chronic ischemia (lack of blood and oxygen), which in turn upregulates VEGF. But if there are low levels of VEGF to begin with, or the body is incapable of producing enough VEGF, this feedback loop may not work, he said.
"This work shows more growing evidence that VEGF has neurotrophic effects," said Carmeliet. The research was published online in Nature Genetics in July by Carmeliet and colleagues in Sweden and the United Kingdom.
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