**1. Introduction**

The interface between the blood circulation and the central nervous system (CNS) comprises complex multicellular structures with unique features that selectively allow or restrict the passage of substances between these compartments. Two distinct blood CNS barriers exist: the endothelial blood-brain barrier (BBB), localized at all levels of the cerebral vascular tree, and the epithelial blood-cerebrospinal fluid barrier, situated at the choroid plexuses within the brain's ventricular system, separating the brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) from the peripheral circulation [1].

The BBB is a term used to describe the unique properties of the microvasculature of CNS. The vascular tree are continuous non fenestrated vessels and contain a series of properties that allow them to tightly regulate the movement of molecules, ions, and cells between the blood and the CNS [2, 3]. The human brain is one of

the most metabolically active organs in the body, under physiological conditions, the human brain receives 20% of the total basal cardiac output and uses 20% of the body's oxygen and glucose [4]. Energy substrates are consumed by the brain from the blood via transport across the BBB, as the brain lacks a metabolic reservoir to store macromolecules for use when needed. In the mammalian brain, cerebral arteries, arterioles, and capillaries supply CNS with blood in response to neuronal stimuli by increasing the rate of cerebral blood flow (CBF), nutrients and oxygen delivery, a mechanism known as neurovascular coupling [5].

The neurovascular coupling requires an integrated multicellular response to provide the perfusion needs for neuronal metabolism [5], different cell types are involved in this action, neurons and astrocytes generate mediators that trigger cellular responses in endothelium cells, pericytes, and smooth muscle cells (SMC), which contribute to vascular response in the BBB permeability. Functionally, these interactions are included in the concept of the neurovascular unit (NVU), which comprises various central and peripheral cell types that contribute to BBB structure and function (**Figure 1**) [6, 7]. However, in pathophysiological states, BBB breakdown and dysfunction leads to leakages of harmful blood components into the cerebral parenchyma, cellular infiltration, and aberrant transport and clearance of molecules [8], which is associated with CBF reductions and dysregulation [9], contributing to neurological effects.

Here, we first examine the cellular components that underlie the establishment of the BBB in NVU. Then, we focus on the cellular components of BBB and transport physiology. Complementary and in a translational way, examine how BBB breakdown and dysfunction related to acute vascular CNS disorders such as ischemic and hemorrhagic stroke, and BBB breakdown and dysfunction relate to neurological deficits and other pathologies in Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS).

#### **Figure 1.**

*(A) The multicellular structure of the neurovascular unit (NVU). The BBB is formed by endothelial cells at the level of the cerebral bed (arterial and venous). These endothelial cells interact with perivascular elements, such as the basal lamina (BMs), smooth muscle cells (SMCs) and astrocytic end-feet processes, perivascular neurons and pericytes to form a functional BBB. (B) The core anatomic elements of the NVU. Created with BioRender.com.*

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membrane [20].

*Blood-Brain Barrier Dysfunction in the Detrimental Brain Function*

The NVU is a relatively recent neuroscience concept, representing the structural and functional multicellular relationship between the brain and blood vessels [5]. The cellular components are the endothelial cells (EC), pericytes, perivascular astrocytes, microglia, the basement membrane (BM), and neuron (**Figure 1**) [10]. The NVU components share intimate and complex associations, and these associations have led to their classification as a single functioning unit. The NVU is responsible for the maintenance of a highly selective BBB and cerebral homeostasis, as well as the control of CBF [11]. Each NVU component seems to play a specific and active role, maintaining the dynamic linkages reciprocally under physiological conditions. **Endothelial cells** are considered the BBB's anatomic basis since they form and tightly seal the wall of all cerebral vessels, thereby building a physical barrier between the blood and the brain parenchyma (**Figure 1**). Two different types of endothelial junctions exist: adherens junctions (AJ) and tight junctions (TJ) [12]. Adherens junctions comprise vascular endothelial (VE) cadherin and neural (N-) cadherin, both acting via homophilic interactions [13]. While VE-cadherin is vital for sealing adjacent endothelial cells, N-cadherin mediates their association with pericytes [13]. TJ contains transmembrane proteins such as claudins, occludins, and junction adhesion molecules, as well as the zona occludens cytoplasmic proteins (ZO). These proteins act collectively to close off interconnecting endothelial cells [14], restricting the paracellular diffusion of hydrophilic substances, even ions; this is a unique feature of the BBB endothelium [11] in the other hand, the neurovascular endothelial cells, in contrast to peripheral endothelial cells, is the low expression of adhesion molecules (e.g. member of the immunoglobulin superfamily VCAM-1), in this sense, immune cells never cross unstimulated BBB in the healthy CNS [15]. Interactions of endothelial cells with other NVU members mediate a decrease in transcytotic activity, downregulation of leukocyte adhesion molecules, and regulation of interendothelial junction stability during development and adulthood [14]. **Pericytes** are mural cells enwrapping capillary blood vessels on their abluminal side. Structurally, pericytes extend processes from their cell body, covering several endothelial cells (**Figure 1**). In contrast to peripheral tissues, the brain has the highest pericyte to endothelial cell ratio [16]. Pericytes are embedded within the basement membrane (BM) of capillary endothelial cells and are thus centrally positioned between endothelial cells, astrocytes, and neurons [3]. In total, pericytes cover a large cerebral vascular area which can reach up to 40% of the neurovascular surface [17]. One of the main functions of pericytes is the control of the vasoreactivity and cerebral blood flow in response to neuronal activity [18]. As a recently explored example, glutamate induces prostaglandin E2 and nitric oxide release, which leads to actively relaxing pericytes to dilate capillaries [19]. Vascular permeability increases with decreasing pericyte coverage, which is partly due to the regulation of endothelial transcytosis. Moreover, other parts of the NVU are also influenced by pericytes, including neurons, immune cells, and the basement

**Astrocytes** are the most abundant cell type in the brain with a variety of functions. Beyond BBB regulation, they participate in synapse formation, uptake and recycling of neurotransmitters and ions, regulation of extracellular potassium levels, nutrition of neurons, and control of inflammatory responses within the CNS [21]. Astrocytes provide a cellular link between the neuronal circuitry and blood vessels. This neurovascular coupling enables astrocytes to relay signals that regulate blood flow in response to neuronal activity; this includes regulating the contraction/dilation of vascular SMC surrounding arterioles and

*DOI: http://dx.doi.org/10.5772/intechopen.94572*

**2. The BBB and the neurovascular unit**
