Daniel Manrique-Castano, Neuroscientist, Germany

16 April 2020

This article was originally published in Spanish at https://hablemosdeneurociencia.com/unidad-neurovascular/

In the scientific community and in the general public there is a strong association between neuroscience and the study of the brain with a particular emphasis: neurons. If we ask anyone which cells make up the brain, they will answer without hesitation: neurons. Indeed, neurons are the best-known member of the central nervous system (CNS) and their properties have been widely studied over the last century. For this reason, their functions in various human activities such as movement, sensation, and cognition are widely known. However, even neuroscientists seem to forget that the brain is made up of much more than just neurons.

In 2016 I participated in the European Conference for Students of Neuroscience (ENCODS 2016) held in Denmark. There, I observed a particular issue. From a sample of almost one hundred doctoral students from all over Europe, about 90% of them were studying neurons. What about endothelial cells, astrocytes, oligodendrocytes, microglia, pericytes, Schwann cells, and others? Only two of the students, including myself, were dedicated to studying astrocytes, for example. The picture in the field of Neuroscience, in general, is not much different. Most efforts to understand the brain focus on the study of various properties of neurons. However, some of us expect this picture to change in the coming years. For at least two decades, neuroscientific literature can be found using the concept of a Neurovascular Unit (NVU) [2] or even a Neurogliovascular Unit [5].

A new integrative concept in Neuroscience: The neurovascular unit

The concept of neurovascular unit reminds us that the brain is composed of a diverse and coordinated cellular community. Phenomena such as consciousness, sleep and wakefulness, perception, and movement are not only the product of neuronal activity; on the contrary, they are the result of the organized action of dozens of cells and factors that direct the brain’s functioning in healthy or pathological conditions. In general, it can be said that the neurovascular unit is composed of at least eight members: microglia, oligodendrocytes, pericytes, astrocytes, neurons, extracellular matrix, endothelial cells, and immune system cells [2]. The architecture of this set is the result of genetically programmed cascades that develop during embryogenesis. Because of their common origins in the embryo, the cells that make up the NVU are susceptible to the same growth factors and share diverse structures and functions. Although individual roles could be indicated for each of the components, it is difficult to define precise and unique roles for each cell type, because many of their functions are interrelated [6].

“The concept of neurovascular unit reminds us that the brain is composed of a diverse and coordinated cellular community.”

Astrocytes and extracellular matrix

Astrocytes are an important cell population in the CNS. In general, it could be said that astrocytes interact indirectly with the entire CNS through the expression of a wide range of receptors for neurotransmitters, cytokines and toxins, and through the release of molecules from the extracellular matrix (ECM) to regulate extracellular water, pH, tissue, and the availability of metabolites, among other factors. Similarly, they have direct contact with the vascular and neuronal system, enveloping the blood vessels to control blood flow and releasing transmitters into the synaptic cleft [1].

The ECM is a compound of about 300 proteins that are organized three-dimensionally in the extracellular space and constitute the extracellular environment in all mammalian tissues. Although their main source are astrocytes, ECM molecules can be secreted by neurons and other glial cells, and their function is to dynamically modulate the entire spectrum of cellular functions, including the integrity and architecture of brain tissue mechanically or through signaling [3]. Particularly, after injury, ECM molecules like Tenascin-C and neurocan are responsible for regulating inflammatory signals in the tissue, and for shaping the fibrotic scar at the injury core.

The neurovascular unit is composed by different cells types 

Microglia and immune cells

Microglia are immune derived cells that conform approximately 20% of the CNS cell population. Like other immune cells such as T cells, microglia play a key role during CNS injury, where they overexpress membrane receptors known as toll-like receptors (TLRs), which play a decisive role in pathophysiological cascades. The functions of microglia and immune cells are linked to the release of cytokines that lead to tissue inflammation, cell death, and blood-brain barrier (BBB) dysfunction. Similarly, microglia express channels of potassium, sodium, and calcium that are related to proliferation, maintenance of membrane potential, pH regulation and cell volume control [5].

Endothelial cells and pericytes

Through tight junctions, Endothelial cells play a critical role in the formation and functioning of the BBB, which controls the supply of nutrients and the removal of potentially toxic components from the brain. However, it is also responsible for preventing potential therapeutic components from entering the brain. For this reason, investigating the mechanisms and permeable properties of BBB is a key point in the development of therapeutic components to treat various pathologies [4].

Finally, pericytes, which are less known, are contractile cells attached to capillary vessels, whose main function is the formation and regulation of BBB and blood flow. In this aspect, it has been observed that a coherent localization of endothelial proteins is achieved only in co-culture with pericytes. It should be noted that the function of pericytes in the healthy and pathological CNS has only recently begun to be explored, making it a novel field of research in Neuroscience. It has been discovered that through their communication with other cells in the NVU, pericytes contribute to the regulation of neurovascular coupling, the entry of immune cells into the CNS after injury, the regulation of angiogenesis and the formation of glial scarring [4].

There is no evidence to indicate that neurons are the main component of the neurovascular unit, and no clear reasons to understand why neuroscience research focuses on them. Perhaps it is just a matter of habit and following a dominant paradigm without sitting down to look at the whole picture. In my oral presentation at ENCODS 2016, I argued to an astonished audience of neuroscience students that neurons are far from being the most important component of the CNS, and that the functioning of the neurovascular unit has astrocytes at its core.

General tissue homeostasis and multiple functions of all cell types are guided by astrocytes and their secreted molecules. At first, of course, researchers are inclined to defend the well-known and widely studied neurons. But when the fact is brought to the table that astrocytes are viable without neurons, but neurons are not without astrocytes; and that astrocytes are able to withstand metabolic stress and provide support to other cells, while neurons are weak and selfish (there is no evidence to support that the function of neurons helps other cells to become viable), the picture looks different.

I still wonder why in a number of studies on brain diseases, attempts are still being made to save neurons and not astrocytes, for example, which are more useful for the general health of the tissue. The truth is, for the time being, that the study of NVU as a whole is in its infancy, and that the concept itself is a much more integrated view of how the CNS works. Whether we will ever manage to unravel its full complexity is something the history books of the future will tell us.

References

[1] Anderson, M. A., Ao, Y., & Sofroniew, M. V. (2014). Heterogeneity of reactive astrocytes. Neuroscience Letters, 565, 23–29. https://doi.org/10.1016/j.neulet.2013.12.030

[2]Dirnagl, U. (2012). Pathobiology of injury after stroke: The neurovascular unit and beyond. Annals of the New York Academy of Sciences, 1268(1), 21–25. https://doi.org/10.1111/j.1749-6632.2012.06691.x

[3] Dzyubenko, E., Gottschling, C., & Faissner, A. (2015). Neuron-Glia Interactions in Neural Plasticity : Contributions of Neural Extracellular Matrix and Perineuronal Nets. Neural Plasticity, 2016, 498037. https://doi.org/10.1155/2016/5214961

[4] Hawkins, B. T., & Davis, T. P. (2005). The Blood-Brain Barrier / Neurovascular Unit in Health and Disease. Pharmacological Reviews, 57(2), 173–185. https://doi.org/10.1124/pr.57.2.4.173

[5] Khanna, A., Kahle, K. T., Walcott, B. P., Gerzanich, V., & Simard, J. M. (2014). Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema. Translational Stroke Research, 5(1), 3–16. https://doi.org/10.1007/s12975-013-0307-9

[6] Muoio, V., Persson, P. B., & Sendeski, M. M. (2014). The neurovascular unit – concept review. Acta Physiologica, 210(4), 790–798. https://doi.org/10.1111/apha.12250

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