In recent years, a possible involvement of blood vessels in the aging brain and in neuronal degeneration has become the focus of interest in various laboratories. After all, it has been known for a long time that circulatory disturbances in the brain correlate with the development of memory disorders. Mild cognitive deficit is most often caused by inadequate blood flow to brain tissue.
Today, I would like to report exciting new findings suggesting a potential therapy for neurodegeneration with vascular endothelial growth factor A (VEGF-A).
As I described in my book on neurodegeneration in section 2.1.3, the blood supply to the approximately 86 billion neurons in our central nervous system is provided by a 650 km network of blood vessels (arteries, capillaries and veins). Thus, no neuron is more than 15 micrometers (µm) away from a blood vessel (for comparison, a human hair is about 50 µm thick). The capillary system of the brain is therefore very dense. After all, it also supplies 20% of the energy carriers absorbed by the organism (although the brain accounts for only 2% of the body weight).
The blood-brain barrier prevents the uncontrolled entry of cells and substances from the blood into the nervous tissue. This is primarily due to the inner lining of the vessels, the endothelium, which represents a flat cell layer sealed by cell adhesions (tight junctions). Between the nerve cells and the vessels are the extensions of the astroglial cells, which are also connected by tight junctions and control the transport of substances to the neurons. Taken together, endothelium, astroglia and neurons form a neurovascular unit. In this context, the endothelium acts as the actual barrier, as it prevents the passage of large macromolecules and whole cells, as well as pathogens (e.g. bacteria).
There is now increasing evidence that blood-brain barrier dysfunction plays a significant role in neurodegenerative diseases. With age, the endothelium becomes more impermeable. As a result, certain vital proteins are less able to enter the brain from the blood. Conversely, proteins that do not normally enter the brain (e.g., albumin, fibrinogen, or autoantibodies) are detectable in older brain tissue and can trigger inflammatory processes. The capillaries are also less permeable to oxygen and sugar.
The endothelium proliferates in response to stimulation by growth factors. This results in the formation of new capillaries and subsequently further vessels. The most important stimulator of angiogenesis is vascular endothelial growth factor A (VEGF-A). It binds to specific receptors, VEGF-R1 and VEGF-R2, which are receptor tyrosine kinases located in the plasma membrane of endothelial cells. Activation of VEGF receptors is particularly relevant in rapidly growing tissues, for example in the context of embryonic development, but also in malignant tumors. VEGF is also important for the regeneration of damaged organs, as it is released during oxygen deficiency (hypoxia). In addition, VEGF-A maintains the endothelium and promotes the survival of nerve cells.
In old age and in Alzheimer's patients, the density of capillaries in the brain decreases by 10-30% (both gray and white matter are affected). It would therefore make sense to stimulate capillary growth via VEGF to counteract reduced blood flow. Indeed, the 1.5-2-fold increase of VEGF-A in the blood circulation by genetic overexpression of the factor in the liver prevents the decrease in capillary density (Grunewald et al., 2021). However, the most exciting finding of this work is that the lifespan of animals treated in this way increased by 40-50%. In all organs studied, a rejuvenation effect occurred with the increased VEGF concentration.
This observation supports the assumption that deficiency of VEGF-A underlies the aging process, which can probably be explained by the increase of a soluble VEGF receptor (sVEGF-R1) in the blood of the older organism (the soluble receptor scavenges VEGF so that it can no longer bind to the VEGF receptors on the endothelium). In addition to the effect on angiogenesis, artificially increasing VEGF-A levels could also slow down the molecular aging process in our cells or suppress the chronic inflammatory response that is particularly seen in the aging brain.
Clinical studies in patients will show whether the effect observed in animal experiments can also be demonstrated in humans. Presumably, VEGF therapy would have to be started before the onset of neuronal degeneration.
References:
Augustin HG, Kipnis J (2021) Vascular rejuvenation is geroprotective. Science 373:490-491
Grunewald M, Kumar S, Sharife H, ..., Keshet E (2021) Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science 373:eabc8479
Image credit: iStock/Storman and iStock/Rasi Bhadramani
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