ReviewThe blood–brain barrier: an overview: Structure, regulation, and clinical implications
Introduction
The blood–brain barrier (BBB) is a diffusion barrier essential for the normal function of the central nervous system. The BBB endothelial cells differ from endothelial cells in the rest of the body by the absence of fenestrations, more extensive tight junctions (TJs), and sparse pinocytic vesicular transport. Endothelial cell tight junctions limit the paracellular flux of hydrophilic molecules across the BBB. In contrast, small lipophilic substances such as O2 and CO2 diffuse freely across plasma membranes along their concentration gradient (Grieb et al., 1985). Nutrients including glucose and amino acids enter the brain via transporters, whereas receptor-mediated endocytosis mediates the uptake of larger molecules including insulin, leptin, and iron transferrin Pardridge et al., 1985, Zhang and Pardridge, 2001. In addition to endothelial cells, the BBB is composed of the capillary basement membrane (BM), astrocyte end-feet ensheathing the vessels, and pericytes (PCs) embedded within the BM (Fig. 1A). Pericytes are the least-studied cellular component of the BBB but appear to play a key role in angiogenesis, structural integrity and differentiation of the vessel, and formation of endothelial TJ Allt and Lawrenson, 2001, Balabanov and Dore-Duffy, 1998, Bandopadhyay et al., 2001, Lindahl et al., 1997. It is believed that all the components of the BBB are essential for the normal function and stability of the BBB.
Section snippets
Tight junctions
Junction complex in the BBB comprises TJ and adherens junction (AJ). The TJs ultrastructurally appear as sites of apparent fusion involving the outer leaflets of plasma membrane of adjacent endothelial cells (Fig. 1B). Freeze fracture replica electron micrographs depict TJs as a set of continuous, anastomosing intramembranous strands or fibrils on P-face with a complementary groove on the E-face. The number of TJ strands as well as the frequency of their ramifications is variable. Adherens
Role of astrocytes in the formation of the blood–brain barrier
A number of grafting and cell culture studies have suggested that the ability of CNS endothelial cells to form a BBB is not intrinsic to these cells, but CNS environment induces the barrier property into the blood vessels. Avascular tissue was transplanted from 3-day-old quail brain into the coelomic cavity of chick embryos; and it was observed that the chick endothelial cells vascularizing the quail brain grafts formed a competent BBB (Stewart and Wiley, 1981). In contrast, when avascular
Intercellular signaling: inductive influence of astrocytes on endothelial cells
Numerous efforts have been directed on defining agents that mediate the induction and maintenance of the BBB. We are reviewing only selected studies here. It has demonstrated in astrocyte–endothelial coculture experiments that TGF-β produced by astrocytes is responsible for the down-regulation of tissue plasminogen activator (tPA) and anticoagulant thrombomodulin (TM) expression in cerebral endothelial cells (Tran et al., 1999). It is plausible that TGF-β secreted by astrocytes may have a role
Pericytes and the BBB
Pericytes (PCs) are cells of microvessels including capillaries, venules, and arterioles that wrap around the endothelial cells. They are thought to provide structural support and vasodynamic capacity to the microvasculature. Importantly, PC loss and microaneurysm formation in PDGF-B-deficient mice have been observed (Lindahl et al., 1997). This suggests that PCs play a key role in the structural stability of the vessel wall. Metabolic injury to PCs in diabetes mellitus is associated with
Fetal brain anatomy and germinal matrix
The wall of the fetal cerebral hemisphere consists the ventricular zone, subventricular zone, intermediate zone, cortical plate, and marginal zone, as described by the Boulder Committee (1970). A localized thickening medial to the basal ganglia in the subventricular zone, which bulges into the lateral ventricle, is referred as the germinal matrix. This periventricular germinal matrix (GM) in human fetuses, located in the region of the thalamostriate groove beneath the ependyma, is densely
Opening of the BBB in pathophysiology
As discussed earlier, under physiologic conditions, the BBB is relatively impermeable. In pathologic conditions, a number of chemical mediators are released that increase BBB permeability. Several of these mediators of BBB opening have been studied in both in vivo and in vitro experiments and include glutamate, aspartate, taurine, ATP, endothelin-1, ATP, NO, MIP-2, tumor necrosis factor-α (TNF-α), MIP2, and IL-β, which are produced by astrocytes Abbott, 2000, Abbott, 2002, Chen et al., 2000,
References (133)
- et al.
Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members
Blood
(2001) - et al.
CNS microvascular pericytes express macrophage-like function, cell surface integrin alpha M, and macrophage marker ED-2
Microvasc. Res.
(1996) - et al.
Radial glial interaction with cerebral germinal matrix capillaries in the fetal baboon
Exp. Neurol.
(1992) - et al.
Neovascularization and the appearance of morphological characteristics of the blood–brain barrier in the embryonic mouse central nervous system
Brain Res. Dev. Brain Res.
(1993) - et al.
Homophilic interaction of junctional adhesion molecule
J. Biol. Chem.
(2000) - et al.
Immunohistochemical and ultrastructural characterization of cortical plate microvasculature in the human fetus telencephalon
Microvasc. Res.
(1999) - et al.
Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo
Neuroscience
(1998) - et al.
Angiogenesis and the blood–brain barrier in solid and dissociated cell grafts within the CNS
Prog. Brain Res.
(1990) - et al.
The influence of cytokines on the integrity of the blood–brain barrier in vitro
J. Neuroimmunol.
(1996) - et al.
Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1
J. Biol. Chem.
(2000)