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Aragón-González, A.;  Shaw, P.J.;  Ferraiuolo, L. Components of the Blood–Brain Barrier. Encyclopedia. Available online: https://encyclopedia.pub/entry/40721 (accessed on 17 December 2025).
Aragón-González A,  Shaw PJ,  Ferraiuolo L. Components of the Blood–Brain Barrier. Encyclopedia. Available at: https://encyclopedia.pub/entry/40721. Accessed December 17, 2025.
Aragón-González, Ana, Pamela J. Shaw, Laura Ferraiuolo. "Components of the Blood–Brain Barrier" Encyclopedia, https://encyclopedia.pub/entry/40721 (accessed December 17, 2025).
Aragón-González, A.,  Shaw, P.J., & Ferraiuolo, L. (2023, February 01). Components of the Blood–Brain Barrier. In Encyclopedia. https://encyclopedia.pub/entry/40721
Aragón-González, Ana, et al. "Components of the Blood–Brain Barrier." Encyclopedia. Web. 01 February, 2023.
Components of the Blood–Brain Barrier
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This entry is adapted from the peer-reviewed paper 10.3390/ijms232315271

The blood–brain barrier (BBB) is a highly specialized and dynamic compartment which regulates the uptake of molecules and solutes from the blood. The neurovascular unit (NVU) has been described as a structure formed by microvascular endothelium, astrocytes, pericytes and neurons that are in physical proximity to the endothelium, basal lamina and parenchymal basement membrane. Each NVU component is intimately and reciprocally linked to each other, sharing several characteristics and establishing an anatomical and functional whole, which results in a highly efficient system regulating cerebral blood flow. 

blood–brain barrier neurodevelopment neurodegeneration therapies

1. Brain Microvascular Endothelial Cells (BMVECs)

BMVECs are a major cellular element of the BBB. They are extremely thin cells and present unique characteristics that distinguish endothelial cells of the brain from the vascular endothelium in the rest of the body, including tight junctions (TJs), absence of fenestrations, fewer or absent pinocytotic vesicles, expression of specialized transporters, and close association with other cell types comprising the NVU. These attributes allow them to tightly regulate the movement of ions, molecules, and cells between the blood and the brain [1].
The TJs are mainly composed of proteins such as ZO-1, -2,- 3, occludins and claudins; adherens junctions (AJs), including cadherins, actinin and catenins, and junctional adhesion molecules, e.g., JAM-1. ZO-1 is located on the cytoplasmic side of the BMVEC plasma membranes and connects the TJs with the cytoskeleton. JAM-1, on the other hand, participates in TJs formation in conjunction with occludin and claudin and is involved in cell-to-cell adhesion. In addition, JAM-1 is involved in leukocyte migration. Therefore, its dysregulation has been associated with alterations of CNS immunity [2]. Additionally, BMVECs express two main types of transporters: efflux transporters [3] and highly specific nutrient/waste transporters [4]. Another remarkable difference between BMVECs and other endothelial cells is their higher content of mitochondria, which generate high levels of ATP used during active transport of ions and fluid [5][6].
Moreover, the quantity of leukocyte adhesion molecules is much lower in BMVECs compared to other endothelial cells, as these are involved in the interactions with leukocytes to regulate their transendothelial migration. In fact, the extremely low level of leukocyte adhesion molecules expressed in BMVECS is directly linked with the inability of immune cells to cross the barrier and enter into the CNS [2].
Interestingly, several biochemical studies have revealed the functional polarity present in the BMVECs, with different expression of enzymes, transporters, receptors and ion channels in the luminal and abluminal membrane surfaces of these endothelial cells to preserve brain homeostasis by controlling the exchanges between the blood and brain compartments [7].
Differences in enzymatic activity have also been found in BMVECs compared with other endothelial cells, with a high concentration of enzymes such as γ-glutamyl transpeptidase, alkaline phosphatase and aromatic acid decarboxylase. These enzymes take part in the assimilation of the neuroactive solutes originating from the blood, thus allowing BMVECs to metabolize drugs and nutrients for presentation to the brain [8].

BMVECs in Brain Vascular Contraction

BMVECs synthetize and release both endothelin-1 (ET-1) and NO which are in balance under healthy circumstances to maintain the function of the vascular tone. The disequilibrium of these molecules is involved in cerebral blood vessel dysfunction, such as in stroke [9]. ET-1 is one of the most potent vasoconstrictors known for mammalian blood vessels, with a relatively low concentration in plasma (0.2–5 pg/mL), while increased amounts have been reported in diseases such as hypertension and diabetes type 2 [10]. Endothelin receptors have been identified on platelets and blood vessels. Two subtypes of ET-1 receptors, ETA and ETB, have been described; however, the predominant subtype in the brain is B [11]. ETB opposes vasoconstriction by stimulating NO formation, acting as a feedback mechanism to limit the vasoconstrictor action of ET-1. NO inhibits platelet aggregation, the expression of adhesion molecules and the production of ET-1 [12]. The vasoconstriction mechanism through which ET-1 decreases the local brain flow is through platelet interaction, whereas a significant increase of ET-1 expression has been linked to haemorrhages [13]. Many physiological processes, including neurotransmission, are promoted by NO, which is mostly synthesized through endothelial NO synthase [14]. Interestingly, it has been reported that endothelial NO synthase knock-out mice have increased levels of amyloid-beta protein (Aβ) precursor, while expression of endothelial NO synthase and excess of NO have been associated with BBB disruption [15]. These data highlight the link between NO dysfunction, BBB disruption and some neurodegenerative disorders such as Alzheimer’s disease (AD) [16].

2. Astrocytes

Astrocytes are the most abundant cells in the brain and play important roles in the establishment and maintenance of the BBB. They occupy a strategic position between capillaries and neurons. Astrocytic end-feet form a coating network around the brain vasculature, the glia limitans, and, together with endothelial cells and pericytes, they form the BBB, separating the bloodstream from the brain parenchyma. Astrocyte dysregulation is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) [17] and AD [18] and paediatric neurological disorders such as Rett syndrome [19].
As mentioned in the previous section, astrocytes are in their immature form during BBB development; mature astrocytes, in fact, are not detected in the human foetal brain stem until the 15th week [20] and in foetal cortex until the 30th [21]. This late development, which continues even postnatally, offers a potential therapeutic window to reverse developmental dysregulation, thus making astrocytes an appealing therapeutic target.
Although the heterogeneity of the astrocyte population across the brain is well known, it is still poorly characterized and little is understood about its impact on BBB function. In the mature barrier, astrocytes secrete cytokines, growth factors and extracellular matrix proteins through their end-feet, including, in particular, proteoglycans of the lectican family and tenascins [22]. Other aspects of glial support include the signalling of reinforcing pathways such as sonic hedgehog protein (Shh), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), retinoic acid (RA) [23]. The role of astrocyte-derived Shh was proposed in maintaining the BBB via a mechanism involving regulation of TJ protein expression by BVMECs [24]. Nevertheless, transcriptomic studies have begun to point out that post-mitotic astrocytes, and not BMECs, represent the primary responders to hedgehog signalling in the adult brain [25]. Astrocytes are also involved in strengthening the TJ, whose maturation is promoted by release of glial cell-derived neurotrophic factor (GDNF), an EC ligand for the GDNF family receptor alpha-1 (GFRA-1).
Furthermore, astrocytes play a crucial role in glutamate homeostasis, which is critical to maintain neuronal function and protect against excitotoxicity. Glutamate is known as the most abundant excitatory neurotransmitter in the mammalian nervous system, but its signalling is also important for the correct functioning of the BBB. Glutamate has been demonstrated to increase the permeability of BMVECs via activation of N-methyl-D-aspartate (NMDA) receptors [26][27]. For this reason, its clinical potential as a modulator of BBB permeability has been extensively explored in the context of neuroprotection and drug delivery [28]. Glutamate is also involved in blood flow regulation, since glutamate-mediated signalling prompts the release of NO from neurons, thus promoting vasodilation, and of arachidonic acid from astrocytes, which can have the double action of vasodilator or vasoconstrictor [29].
Considering the pivotal role of glutamate in the CNS and the injurious effects of its excessive accumulation in the synaptic cleft, astrocytes express excitatory amino acid transporters (EAATs), i.e., Na+-dependent glutamate transporters, in order to keep the concentration of glutamate tightly controlled in the extracellular space [30]. In addition, astrocytes are also involved in BM regulation by using ammonia in the synthesis of glutamine, metabolizing short-chain fatty acids, taking part in the regulation of brain nitrogen metabolism, and, finally, preventing the accumulation of ammonia, glutamine and glutamate in the CNS [31].
Another critical role of astrocytes in maintaining BBB function is the release of TGF-β, which regulates multiple biological processes, adult stem cell differentiation, immune regulation, apoptosis, and inflammation [32]. In addition to the pivotal role of TGF-β in TJ and blood vessel formation described above, TGF-β also downregulates endothelial anticoagulant factors, such as thrombomodulin, and increases blood flow under pathological conditions [33].
Similarly involved in fluid exchange and regulation, aquaporin-4 (AQP4) is the most abundantly expressed water channel in the brain and is predominantly expressed in the end-feet of astrocytes [34]. AQP4 regulates water permeability and plays an important role in neuroimmunological functions too, but its role in brain physiology has remained elusive for years. AQP4 controls bidirectional fluid exchange [35] and has been linked to several pathological processes including paediatric brain neoplasms with dysfunctional BBB [36] and the neuroimmunological disorder neuromyelitis optica [37].

3. Pericytes

Pericytes coexist with the astrocytes in the abluminal compartment to maintain the BBB properties [38], located within the NVU between endothelial cells, astrocytes, and neurons. The relevant role of pericytes in the developmental phase of the barrier and their interaction with endothelial cells through PDGF-β signalling during the process has been described above.
It was shown that the number of pericytes involved in the barrier inversely correlates with its permeability, thus a decrease in the number of pericytes correlates with an increase in the BBB permeability [39]. In addition, reduction in pericyte coverage across the BBB is inversely correlated with ageing [40] and neurodegeneration, as in ALS [41].
In the case of pericyte loss, as it occurs in ageing, brain injury or neurodegeneration, these cells can actively adapt to ensure endothelial coverage by extending their wide-reaching processes [42]. Pericytes are major regulators of cerebral blood flow due to their sensitivity to glutamate signalling, which promotes the release of vasodilators such as NO and prostaglandin E2 [43]. They also help direct astrocyte foot projections and are responsible for reducing levels of leukocyte adhesion molecules [44].
Additionally, pericytes control the expression of TJ and AJ proteins and their alignment. They also regulate transendothelial vesicle trafficking across the barrier which is implicated in the transport of nutrients and essential molecules [44]. These cells also play a major role in blocking the entrance of xenobiotics, including therapeutic compounds, into the brain, which makes them a potential target for drug delivery [45].
The role of pericytes in neuroinflammation has been demonstrated by Olson et al. [46] in conditional PDGFR-β knock-in mice. These researchers showed the way in which a PDGFR-β-induced immune response could modulate the inflammatory properties of endothelial cells, leading to increased leukocyte adhesion and transmigration. They also revealed that amplified PDGFR-β signalling led to higher pericyte coverage of blood vessels and induced changes in pericyte differentiation. On the other hand, pericyte degeneration results in BBB breakdown with the accumulation of neurotoxic molecules leaking from the blood [44].

4. Basement Membrane (BM)

The BM is the non-cellular component of the barrier and it is a unique form of extracellular matrix. Its main functions are structural support, cell anchoring and signal transduction [47]. There are two types of BMs separating endothelium from astrocytes. One of the membranes is composed of fibronectin, collagen type IV, nidogen, perlecan and laminin and it is denominated as the endothelial BM. The other one is the perivascular glia limitans, also known as astroglial or parenchymal BM and is formed by fibronectin, agrin and laminins [48]. Consequently, the most important biochemical components of the BM are collagen type IV, fibronectin and laminin.
Collagen-IV and fibronectin are secreted by the cellular components of the NVU. Collagen-IV, the most abundant component of the BM, maintains BM stability by retaining other protein components such as laminin, perlecan and nidogen. Six collagen-IV isoforms have been identified of which collagen-IV α-1/2 are present in almost all BMs and are highly conserved across species [49]. Nonetheless, there is evidence that collagen-IV is not necessary for early embryonic development, but it is indispensable for the structural integrity of the BMs at later stages [50]. To exemplify the importance of collagen-IV α-1 in BMVECs and astrocytes, mutations affecting the coding gene contribute to cerebrovascular defects resulting in intracerebral haemorrhages [51].
On the other hand, fibronectin stimulates the proliferation and survival of the endothelial cells in the BBB [52] and, in fact, both fibronectin and collagen-IV knock-out mice are embryonically lethal. Defects in the mesoderm, impaired neural tube and vascular development are caused by the absence of fibronectin [53], while collagen-IV deficient mice display structural deficiencies in the BMs with impaired integrity of Reichert’s membrane, a basement heath between the parietal endoderm cells and trophoblast cells.
BMVECs, pericytes and astrocytes synthetize different laminin isoforms. There is a cell-specific expression pattern, hence laminin shows differential distribution between endothelial and parenchymal BMs. As an example, astrocytes produce different laminin isoforms depending on their BM location. Hence, laminin-211 is most abundant in the parenchymal membrane and laminins-411/511 are predominantly expressed in the endothelial membrane [54]. Deletion of laminin full isoforms is lethal during embryonic development. Similarly to fibronectin mutant mice, laminin-211 deletion leads to intracerebral haemorrhage and also age-dependent BBB breakdown [55].
To analyse the significance of laminin in the regulation of the BBB, Menezes et al. [56] generated mice lacking expression of the laminin α2 subunit within the laminin-211 heterotrimer expressed by astrocytes and pericytes. They reported altered integrity and composition of the endothelial basal lamina, inappropriate expression of embryonic vascular endothelial protein MECA-32, reduced pericyte coverage, and TJ abnormalities. Their data reveal the role of laminin in regulating the interactions of the NVU cellular components within the BBB.
The effect that lack of laminin chains has on the BM and BBB integrity was explored in several studies, but the mechanisms driving these phenomena are still largely unknown (see Yao et al. for a detailed review [57]).

5. Transport across the BBB

The BBB is lipophilic in nature, hence hydrophobic molecules and gases such as CO2 or O2 can cross it by passive diffusion [58]. However, only solutes of a molecular weight below 400 Daltons (Da) are able to circulate freely through the BBB endothelium [59]. Because it isolates the brain from the rest of the body, many polar nutrients are needed but cannot diffuse across the barrier. Thus, the main factors that influence the ability of circulating molecules to cross the BBB are their polarity and their size.
Additionally, the TJs forming the BBB act as a barrier to segregate transporters to the abluminal or luminal membrane face, thus preventing their movement across the endothelium and maintaining BBB polarity. Some transporters are present on both sides of the membrane or just in one of them, depending on the brain requirements for nutrients and the region [38].
In addition to passive transport, multiple molecules can be shuttled across the BBB through a variety of ion channels and selective transporters. The main transport mechanisms can be divided into endothelial cell and pericytal transport with machineries across both cell types including active efflux [60], carrier-mediated (CMT [61]) ion-transport [62] and receptor-mediated transport (RMT) [63], with exception of active efflux, which is a specific property of BMVECs. In addition to these, there is also a BMVEC/pericyte independent mechanism, vascular-mediated transport [64].
As mentioned before, BMVECs express two main categories of transporters: efflux transporters (i.e., ABC- and EEAT-transporters), which transport lipophilic compounds, and nutrient transporters, regulating the exchange of nutrients and removal of waste products. For example, essential nutrients such as glucose or amino acids are transported across the barrier by specific solute carriers to supply the essential substrates for brain metabolism [65].
These transport mechanisms and their functional relevance in health, together with their role in many disorders such as AD [66], ALS [67], Huntington’s disease [68], schizophrenia [69], Parkinson’s disease [70] and microcephaly [71], among others, have been extensively described previously [72].

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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Ana Aragón-González , Pamela J. Shaw , Laura Ferraiuolo
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