Neurovascular unit
The neurovascular unit comprises the components of the brain that collectively regulate cerebral blood flow in order to deliver the requisite nutrients to activated neurons. The NVU addresses the brain's unique dilemma of having high energy demands yet low energy storage capacity. In order to function properly, the brain must receive substrates for energy metabolism–mainly glucose–in specific areas, quantities, and times. Neurons do not have the same ability as, for example, muscle cells, which can use up their energy reserves and refill them later; therefore, cerebral metabolism must be driven in the moment. The neurovascular unit facilitates this ad hoc delivery and, thus, ensures that neuronal activity can continue seamlessly.
The neurovascular unit was formalized as a concept in 2001, at the inaugural Stroke Progress Review Group of the National Institute of Neurological Disorders and Stroke. In prior years, the importance of both neurons and cerebral vasculature was well known; however, their interconnected relationship was not. The two were long considered distinct entities which, for the most part, operated independently. Since 2001, though, the rapid increase of scientific papers citing the neurovascular unit represents the growing understanding of the interactions that occur between the brain's cells and blood vessels.
The neurovascular unit consists of neurons, astrocytes, vasculature, the vasomotor apparatus, and microglia. Together these function in the homeostatic haemodynamic response of cerebral hyperaemia. Cerebral hyperaemia is a fundamental central nervous system mechanism of homeostasis that increases blood supply to neural tissue when necessary. This mechanism controls oxygen and nutrient levels using vasodilation and vasoconstriction in a multidimensional process involving the many cells of the neurovascular unit, along with multiple signaling molecules. The interactions between the components of the NVU allow it to sense neurons' needs of oxygen and glucose and, in turn, trigger the appropriate vasodilatory or vasoconstrictive responses. Neuronal activity as well as astrocytes can therefore participate in CNV, both by inducing vasodilation and vasoconstriction. Thus, the NVU provides the architecture behind neurovascular coupling, which connects neuronal activity to cerebral blood flow and highlights the interdependence of their development, structure, and function.
File:Neurovascular unit.jpg|upright=1.2|thumb|A schematic of the neurovascular unit, where astrocyte processes surround the capillary basement membrane and pericytes, creating the glia limitans. Also, resident in the perivascular space are antigen-presenting cells and border-associated macrophages.
The temporal and spatial link between cerebral blood flow and neuronal activity allows the former to serve as a proxy for the latter. Neuroimaging techniques that directly or indirectly monitor blood flow, such as fMRI and PET scans, can, thus, measure and locate activity in the brain with precision. Imaging of the brain also allows researchers to better understand the neurovascular unit and its many complexities. Furthermore, any impediments to the function of the neurovascular system will prevent neurons from receiving the appropriate nutrients. A complete stoppage for only a few minutes, which could be caused by arterial occlusion or heart failure, can result in permanent damage and death. Dysfunction in the NVU is also associated with neurodegenerative diseases including Alzheimer's and Huntington's disease.Function
Anatomical components
The neurovascular unit is made up of vascular cells, glia, and neurons with synaptic junctions for signaling. Cerebral vessels, namely arterioles and the perivascular compartment, form the network of the NVU. Arterioles are made up of pial vessels and arterioles, and the perivascular compartment includes perivascular macrophages in addition to Mato, pial, and mast cells. Cerebral blood flow is a critical component of this overall system and it is facilitated by the neck arteries. Segmented vascular resistance, or the amount of flow control that each section of the brain maintains, is measured as the ratio of the blood pressure gradient to blood flow volume. The blood flow within the NVU is a low resistance channel that allows blood to be distributed to different parts of the body. The cells of the NVU sense the needs of neural tissue and release many different mediators that engage in signaling pathways and initiate effector systems such as the myogenic effect; these mediators trigger the vascular smooth muscle cells to increase blood flow through vasodilation or to reduce blood flow by vasoconstriction. This is recognized as a multidimensional response that operates across the cerebrovascular network as a whole.Blood–brain barrier
The cells of the neurovascular unit also make up the blood–brain barrier, which plays an important role in maintaining the microenvironment of the brain. In addition to regulating the exit and entrance of blood, the blood–brain barrier also filters toxins that may cause inflammation, injury, and disease. The overall microvasculature unit functions as a defense for the central nervous system. Encompassed within the BBB are two types of blood vessels: endothelial and mural cells. Endothelial cells form the wall of the BBB, while mural cells exist on the outer surface of this layer of endothelial cells. The mural cells also have their own abluminal layer which hosts pericytes that work to maintain the permeability of the barrier, and the epithelial cells filter the amount of toxins entering. These cells connect to different segments of the vascular tree that exist within the brain.Neurovascular coupling
Cellular processes critically rely on the production of adenosine triphosphate, which requires glucose and oxygen. These need to be delivered to areas in the brain with consistency via cerebral blood flow. In order for the brain to receive enough blood flow when in high demand, coupling occurs between neurons and CBF. Neurovascular coupling encompasses the changes in cerebral blood flow that occur in response to the level of neuronal activity. When the brain needs to exert more energy, there is an associated increase in the level of blood flow to compensate for this. The brain does not have a place where it stores energy, and, therefore, the response of blood flow has to be immediate so that crucial functions for continued life can persist. Difficulties arise when angiotensin proteins are present in higher concentrations, as there is an associated increase in blood flow that leads to hypertension and potential disorders. Furthermore, modern imaging techniques have allowed researchers to view and study cerebral blood flow in a noninvasive manner. However, imaging deep brain structures in vivo is challenging. Therefore, NVC can be studied on ex vivo brain slices maintained in survival conditions. Ultimately, neurovascular coupling promotes brain health by moderating proper cerebral blood flow. There is still much more to be discovered about it, though; and, due to the difficulty of in vivo research, the growing body of knowledge on neurovascular coupling relies heavily on ex vivo techniques for imaging the neurovascular unit.Imaging
The neurovascular unit enables imaging techniques to measure neuronal activity by tracking blood flow. Various other types of neuroimaging also allow the NVU itself to be studied by providing visual insights into the complex interactions between neurons, glial cells, and blood vessels in the brain.Fluorescence microscopy
Fluorescence microscopy is a widely used imaging technique that utilizes fluorescent probes to visualize specific molecules or structures within the neurovascular unit. It allows researchers to label and track cellular components, such as neurons, astrocytes, and blood vessel markers, with high specificity. Fluorescence imaging offers excellent spatial resolution, allowing for detailed visualization of cellular morphology and localized molecular interactions. By using different fluorophores, researchers can simultaneously examine multiple cellular components and molecular pathways of the neurovascular unit. However, limited tissue penetration depth, photobleaching, and phototoxicity negatively impact the potential for long-term imaging studies.provides details of the neurovascular unit at the nanometer scale by using a focused beam of electrons instead of light, enabling higher resolution imaging. Transmission electron microscopy images thin tissue sections, providing detailed information about the fine cellular structures, including synapses and organelles. Scanning electron microscopy, on the other hand, provides 3D information by scanning a focused electron beam across the sample's surface, allowing for the visualization of the topography of neurovascular unit components. Electron microscopy techniques are, thus, invaluable for studying the precise cellular and subcellular interactions within the NVU. However, it requires sample preparation involving fixation, dehydration, and staining, which can introduce artifacts, and it is not suitable for live or large-scale imaging due to its time-consuming nature.Magnetic resonance imaging
is a non-invasive imaging technique that uses strong magnetic fields and radio waves to generate detailed images of the brain's anatomy and function. It can provide information about blood flow, oxygenation levels, and structural characteristics of the neurovascular unit. The functional MRI allows researchers to study brain activity by measuring changes in blood oxygenation associated with neural activity, thus classifying it as a blood-oxygen-level-dependent imaging technique. Diffusion MRI provides insights into the brain's structural connectivity by tracking the diffusion of water molecules in its tissue. MRI, in general, has excellent spatial resolution and can be used for both human and animal studies, making it a valuable tool for studying the neurovascular unit in vivo. It has limited temporal resolution, though, and its ability to visualize finer cellular and molecular details within the neurovascular unit is relatively lower compared to microscopy techniques.