The role of vascular endothelial growth factor (VEGF)-B, a close relative of the angiogenic growth factor VEGF-A, has remained something of a mystery. A new study suggests that VEGF-B protects motor neurons from apoptosis in a rodent model of amyotrophic lateral sclerosis (ALS), but doesn’t provoke the unwanted vascularization that is a worrisome side effect of VEGF-A treatment. Writing in yesterday’s Journal of Neuroscience, joint first authors Koen Poesen and Diether Lambrechts, of the Flanders Institute for Biotechnology (VIB) in Leuven, Belgium, suggest that VEGF-B has potential as a mitigator of ALS symptoms.
The researchers chose to investigate VEGF-B because of the important role VEGF-A, also known simply as VEGF, plays in ALS. In 2001, Peter Carmeliet, also at VIB and principal investigator on the current study, and colleagues discovered that reduced VEGF-A expression in the spinal cord led to ALS-like symptoms (see Oosthuyse et al., 2001 and ARF related news story). Since then scientists have found that excess VEGF-A delays neurodegeneration and extends survival of a mouse model of ALS (Wang et al., 2007; Azzouz et al., 2004; and see ARF related news story), and that a mutation in the VEGF-A promoter is associated with risk for ALS in men (Lambrechts et al., 2008). “It was logical to also consider analyzing the other VEGF family members,” Carmeliet said.
Unlike VEGF-A, VEGF-B shows little angiogenic activity, and its role has been “enigmatic,” Carmeliet said. VEGF-B knockout mice are viable and fertile, exhibiting relatively subtle cardiac defects (Bellomo et al., 2000). However, VEGF-B has been shown to block apoptosis in retinal and brain neurons (Li et al., 2008). The current study is the first to link VEGF-B to motor neuron degeneration.
The researchers crossed VEGF-B-null mice with mice expressing mutant human superoxide dismutase 1 (SOD1), which causes about 20 percent of familial ALS cases. Such mice are a common model for the disease. The mSOD1 mice lacking VEGF-B failed a rotarod test two weeks before control mSOD1 mice, suggesting that VEGF-B plays a protective role. Similarly, mSOD1 mice with a kinase-dead version of the VEGF-B receptor VEGFR-1 failed the rotarod test nine days earlier than their littermates with active VEGFR-1.
The scientists also found that motor neurons from wild-type rat and mouse embryos survived longer in culture when treated with VEGF-B. The cell survival was similar to murine cultures treated with other growth factors. Growing mouse motor neurons with a feeder layer of astrocytes, the researchers then discovered that VEGF-B was neuroprotective as long as the neurons themselves had the proper receptor; VEGFR-1 in the astrocytes was unimportant. This suggests that VEGF-B exerts its protective effect directly on motor neurons.
Could VEGF-B turn into a potential therapy for ALS? Currently, there is no treatment for the disease, which destroys motor neurons and gradually paralyzes patients. Carmeliet’s results hint that VEGF-B might protect motor neurons in vivo. The scientists tested this hypothesis by giving VEGF-B to rats carrying mutant SOD1. Poesen and colleagues used surgically implanted osmotic minipumps to deliver recombinant mouse VEGF-B to the left lateral brain ventricle at a dose equivalent to 0.2 micrograms per kilogram per day. Treatment began with 60-day-old rats, before the onset of symptoms. Compared to rats receiving only artificial cerebrospinal fluid, the VEGF-B rats survived 15 days longer. They also took 11 more days to fail the rotarod test, although this effect was not statistically significant.
Carmeliet speculates that there might be a more pronounced effect with higher doses of VEGF-B. The recombinant protein is expensive because it’s tricky to make; it sticks together and often folds improperly. Had he the funds, Carmeliet said, he would have tested doses 10-fold, or even 100-fold higher than what was used in the study.
Nevertheless, the current study suggests that VEGF-B, while not essential for normal neural function, springs into action to protect neurons that are injured or diseased. Carmeliet thinks it likely acts by inhibiting apoptosis of the damaged cells, allowing them to function for longer before giving out. VEGF-B could still have a role in healthy animals, and that role remains unclear. “Things tend to have some function,” said David Greenberg of the Buck Institute for Aging in Novato, California. He speculates that VEGF-B’s function might overlap with VEGF-A’s.
“This is a very comprehensive study; the results are very solid,” said Kunlin Jin, also of the Buck Institute. “It opens a new avenue for the treatment of neurodegeneration.” A clinical trial of VEGF-A as therapy for ALS is due to begin in Belgium this autumn, Carmeliet said, under the direction of Wim Robberecht, also at the Flanders Institute, and Neuronova, a biopharmaceutical company in Stockholm, Sweden. However, in contrast to VEGF-B, VEGF-A has side effects, including angiogenesis and potential weakening or perforation of the blood-brain barrier, which may limit its use. In a follow-up study, Carmeliet plans to test a combined treatment with both growth factors, which he suspects might be effective at lower levels of VEGF-A, thus minimizing side effects.
Carmeliet notes that VEGF-B has gotten little attention compared to VEGF-A. A PubMed search finds thousands of VEGF-A papers, but only a couple of hundred on VEGF-B. “Because it doesn’t have the same angiogenic potential, everyone has lost interest in this gene,” he said. “I hope that this paper will prime some interest in the field so that people will study this molecule in more detail.”—Amber Dance.
Amber Dance is a freelance writer living in Los Angeles.
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