. Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. J Neurosci. 2008 Oct 15;28(42):10451-9. PubMed.

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  1. VEGF-B, a New Hope for ALS?
    More than 10 years ago, when I joined Dr. Ulf Eriksson’s laboratory in Stockholm as a postdoctoral fellow to try to delineate the biological function of VEGF-B by phenotyping VEGF-B deficient mice, I was excited.

    Who would not be excited? VEGF-A was then, and still is, right in the spotlight of the medical research field. Loss of even a single allele of VEGF-A caused early embryonic lethality in mice (1,2). VEGF-B, as a newly discovered VEGF-A homolog at that time, might prove to be equally, if not more, important, I thought.

    However, the subsequent journey to reveal the biological function of VEGF-B has been largely full of disappointments. As a VEGF-A homolog, VEGF-B failed to produce most of the functionality of VEGF-A, for example, inducing new blood vessel growth and blood vessel permeability, etc. Further, loss of VEGF-B does not seem to matter greatly, since VEGF-B-null mice appear largely healthy (3). Years of work investigating the function of VEGF-B had mostly led to negative findings.

    Is VEGF-B a redundant molecule? This was suspected.

    I am happy to say that perhaps now is the time to answer that question with greater confidence.

    The answer is no.

    Even though VEGF-B does not seem to be critically required in normal physiology (3), VEGF-B plays an important role in diseased conditions, such as in amyotrophic lateral sclerosis (ALS), as recently reported by Dr. Pater Carmeliet’s group (4). In an ALS mouse model, VEGF-B deficiency accelerated the onset of this devastating disease and shortened the lifespan of the diseased animals (4). On the contrary, VEGF-B186 protein treatment not only slowed down motor neuron degeneration in ALS rats but also increased their lifespan (4). More importantly, VEGF-B186 does so without affecting the vascular system, in contrast to VEGF-A. Indeed, it is also recently reported that VEGF-B167 protein treatment protected challenged neurons in both the retina and brain without interfering with the blood vessel system (5). Based on these findings, may we now have another good reason to be optimistic in the battle against ALS?

    As for most scientific findings, many questions follow.

    In this study from Dr. Carmeliet’s group (4), VEGF-B186 protein was administered to the ALS rats approximately 30 days before onset of the disease and rescued motor neurons from apoptosis. This supports the theory that VEGF-B186 has a therapeutic value in the prevention of ALS. However, it is highly desirable to know whether VEGF-B186 could do so when administered after the onset of the disease, a situation that is more clinically relevant.

    Since VEGF-B167, as compared with VEGF-B186, is the naturally more abundant isoform of VEGF-B expressed in the neural system and in most other organs (6), and since both systemic and topical delivery of VEGF-B167 protein protected the retina, brain, and heart in pathological conditions (5,7), there is a good reason to test whether this naturally more abundant isoform of VEGF-B protein could also save motor neurons from dying, and if so what efficacy will exist as compared with VEGF-B186.

    Given its unique nature of being “inert” in most conditions (8), and therefore having a unique safety profile, together with its potent neuroprotective effects, it would not be surprising to soon note an aggressive research effort to investigate the therapeutic potential of VEGF-B gene and cell therapy in treating different types of neurodegenerative diseases, such as ALS.

    References:

    . Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996 Apr 4;380(6573):439-42. PubMed.

    . Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435-9. PubMed.

    . Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation. 2001 Jul 17;104(3):358-64. PubMed.

    . Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. J Neurosci. 2008 Oct 15;28(42):10451-9. PubMed.

    . VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats. J Clin Invest. 2008 Mar;118(3):913-23. PubMed.

    . Isoform-specific expression of VEGF-B in normal tissues and tumors. Growth Factors. 2001;19(1):49-59. PubMed.

    . Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium. Arterioscler Thromb Vasc Biol. 2008 Sep;28(9):1614-20. PubMed.

    . Novel VEGF family members: VEGF-B, VEGF-C and VEGF-D. Int J Biochem Cell Biol. 2001 Apr;33(4):421-6. PubMed.

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