Vascular Endothelial Growth Factor (VEGF)

VEGF Family12
Image Unavailable

Vascular endothelial growth factor (VEGF) has various different sub groups with a primary function of promoting angiogenesis as well as vascularogenesis. In addition to causing proliferation of blood cells in the body, VEGF also has effects on the brain particularly in the hippocampus where various studies have shown that overexpression of this molecule leads to neurogenesis1,11. In addition to promoting neuronal wellbeing, VEGF protects the brain from atrophic processes that occur during periods of extreme stress and depression7. This growth factor has been targeted for numerous therapeutic purposes where blockage and overexpression have proven effective in treating various ailments4. There are numerous pathways which VEGF works through and in turn illicits different responses within the individual. Although this molecule is an antagonist to stressors, stressful scenarios tend to repress the expression of VEGF and in some individuals this results in clinically diagnosed diseases and various stages of depression.

Neurogenesis and Neuromodulation

Neurogenesis

The proliferation of new neurons is vital in maintaining a person’s mental health throughout their lifetime and even through adulthood. The current model for neural proliferation shows that astrocytes in the subventricular zone (SVZ) act as neural stem cells with the ability to produce neural precursor cells which can then migrate to other regions of the brain to differentiate10. VEGF does not only to modulate neurogenesis, but also alters the hippocampus to accommodate this increase in neuronal proliferation. Since VEGF is a vascular growth factor, overexpression of this molecule will result in physical changes in the hippocampus, primarily being an increase in hippocampal vascular density6. With the increase in vascular density, a higher rate of neuronal proliferation is able to be sustained for a period of time even when VEGF levels return to normal6.

VEGF Pathway13
Image Unavailable

The primary pathway which VEGF functions through in the central nervous system is through the Flk-1 receptor which will in turn lead to the phosphorylation of a number of other kinases downstream8. This pathway is known to stimulate neurogenesis and also causes VEGF to function as a neuronal survival factor outside of the periphery8. Since VEGF is not seen at consistently high levels in the body, its expression is increased when parts of the body are compromised since this affects more than just neurons. A study has shown that VEGF does act through both paracrine and autocrine signalling8. Autocrine signalling is supported by the fact that under stressful conditions, the phosphorylation of ERK, p90RSK and STAT 3am, which are all downstream receptors, is increased8. Increase in the activity of these pathways shows that VEGF is vital in activating other pathways to help mediate a stressor. Neurons also have the capability of secreting VEGF while under stress as a method of promoting survival of itself as well as surrounding neurons lending to the function of VEGF as a paracrine signalling molecule as well8.

In mice VEGF has been found to work through Flt1, KDR and neuropilin (nrp)9. The use of a selective ligand for Flt1 ruled it out as a mediator of this pathway since it was still functional, however the presence of mKDR was able to antagonize the effects of VEGF indicating that KDR was the mediator 9. Further studies have shown that mKDR inhibits learning and thus confirms that KDR functions as the mediator in this pathway. While VEGF is a focused activator of this mediator, other factors activating this mediator can be important in promoting neurogenesis.

Neuromodulation

VEGF also plays an important role in actively shaping neurons that already compose our brains. VEGF has a role in actively shaping not just immature neurons, but mature neurons which many believed to be unmalleable6. A study done on mice following a stroke and administered atorvastatin showed that not only did VEGF expression increase, but that new neurons were formed in damaged areas as well as promoting their differentiation3. This is another method where VEGF protects the brain from being permanently damaged via repair mechanisms. Neurogenesis and neuronal plasticity are two separate entities which are often coupled and complement one another but have different effects on memory and learning. Having a high rate of neurogenesis is not always representative of one’s ability to learn since this is dependent on neurons differentiating in order to retain specific information. VEGF does play a role in neuronal plasticity exemplified by an experiment done on mice where depression was induced via the helplessness model4. Administering VEGF, which has been found to mimic the effect of some anti-depressants, yielded an immediate response indicating that VEGF functions beyond promoting the growth of new neurons and towards the likelihood of shaping pre-existing neurons4.

In order for learning to occur, long term potentiation (LTP) has to happen in order to consolidate memories. While VEGF does enhance both memory and neurogenesis, it is possible to maintain the rate of neurogenesis but decrease the rate of LTP by blocking VEGF in the periphery since this would not allow rates of neural proliferation to go down below baseline rates6. While it is confirmed that VEGF has positive effects on memory, the link to memory modulation is unclear to whether the process is direct or indirect6.

Neuroprotection

VEGF is most effectively administered through a transgenic implant within the organism rather than through serum. There are vascular endothelial cells within the brain leading to increased proliferation during periods of overexpression of VEGF1. The increased proliferation of vascular endothelial cells lends itself to implying that VEGF plays a vital role in protecting the brain during periods of stress, particularly ischemia1. Endothelial cells have been shown to promote proliferation of neural stem cells in turn leading to neurogenesis2.

A common role neuroprotection has in the brain is against stress which has been seen to negatively affect neurotrophins in the brain such as VEGF which may be the result of degradation of certain regions in the brain7. Up regulation of certain factors resulting in the increased expression of VEGF may be used since the Flk-1 pathway in VEGF does promote neurogenesis and will in turn prevent regions of the brain from degrading from stress induced responses4.

VEGF can also help the brain recover in the event of a stroke where a region of the brain has been deprived of oxygen and neurons will in turn perish. The physical replacement of neurons rather than reprogramming is vital in promoting homeostasis of the brain, however in some cases the damage is too great for VEFG and other neurotrophic factors to repair leaving permanent damage due to the stressor. In the event of a stroke, VEGF can also promote neural plasticity in addition of neural proliferation3. This will aid recovery after a stroke by helping immature neurons differentiate at a faster rate.

Therapeutic purposes

In addition to promoting neuronal growth and improving memory, VEGF could be used an antidepressant. This molecule is already used in a number of therapeutic purposes ranging from stroke rehabilitation to Alzheimer’s disease treatment and blockage of this molecule has proven effective in slowing down tumour growth4. It was believed that neurogenesis was necessary in alleviating depression and VEGF was capable of doing this however VEGF can also work through a pathway that is independent of neurogenesis indicating that other factors are capable of relieving depression as well6. This opens up the door for the production of antidepressants using VEGF, however if an effective treatment for depression using the neurogenic pathway can be made, many without depression will want to take the treatment in hopes of accelerated neurogenesis.

Role of exercise

Effect of VEGF on mouse hippocamppi 14
Image Unavailable

Stress has been observed to negatively affect VEGF levels where it is down regulated and thus will not aid in the consolidation of memory5. Stressors that are a detriment to memory can come in various forms such as anxiety, depression and exhaustion, all of which suppress the expression of VEGF. As noted earlier, some antidepressants have been shown to temporarily reverse the effects of stress on memory4. The odd link between VEGF expression and exercise is that exercise is a stressor on the body but is a positive regulator of VEGF5. Studies on mice have shown that mice that ran on a running wheel showed greater levels of VEGF in the periphery in comparison to mice who did not exercise and thus displayed greater levels of neurogenesis5. While other growth factors such as IGF-1 and FGF-2 are released during exercise and play an important role in neurogenesis, blockage of VEGF in these cases brings rates of neural proliferation down to baseline levels comparable to mice who did not exercise4,7. This indicates that VEGF does not play a central role in maintaining levels of neurogenesis in the periphery but is involved in increasing levels of neurogenesis meaning that activities that stimulate the release of VEGF will promote neural growth while remaining stagnant will not be detrimental to one’s mental health.

Bibliography
1. Wang, Y.Q., Guo, X., Qui, M.H., Feng, X.Y., Sun, F.Y. VEGF overexpression enhances striatal neurogenesis in brain of adult rat after a transient middle cerebral artery occlusion. J Neurosci Res 85, 73-82 (2006).
2. Shen, Q., et al. Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells. Science 304, 1338-1340 (2004).
3. Chen. J., et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cerebr Blood F Met 25, 281-290 (2005).
4. Warner-Schmidt, J.L., Duman, R.S. VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 8, 14-19 (2008).
5. Fabel, K., et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18, 2803-2812 (2003).
6. Licht, T., et al. Reversible modulations of neuronal plasticity by VEGF. P Natl Acad Sci USA 108, 5081-5086 (2011).
7. Clark-Raymond, A., Halaris A. VEGF and depression: A comprehensive assessment of clinical data. J Psychiat Res 47, 1080-1087 (2013).
8. Ogunshola, O.O., et al. Paracrine and Autocrine Functions of Neuronal Vascular Endothelial Growth Factor (VEGF) in the Central Nervous System. J Biol Chem 277, 11410-11415 (2002).
9. Cao, L., et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36, 827-835 (2004).
10. Lledo, P.M., Alonso, M., Grubb, M.S. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7, 179-193 (2006).
11. Jin, K., Zhu, Y., Sun, Y., Mao, X.O., Xie, L., Greenberg, D.A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. P Natl Acad Sci USA 99, 11946-11950 (2002).
12. Ferrara, N., Gerber, H.P., LeCouter, J. (2002). The biology of VEGF and its receptors. Nature Medicine, 9, 669-676. http://www.nature.com/nm/journal/v9/n6/fig_tab/nm0603-669_F2.html.
13. Warner-Schmidt, J.L., Duman, R.S. (2008). VEGF as a potential target for therapeutic intervention in depression. Current Opinion in Pharmacology, 8, 14-19. http://www.sciencedirect.com/science/article/pii/S1471489207001841
14. Licht, T., et al. (2011). Reversible modulations of neuronal plasticity by VEGF. PNAS, 108, 5081-5086. http://www.pnas.org/content/108/12/5081.full

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License