In Search of the Astrocytic Factor(s) Modulating Blood–Brain Barrier Functions in Brain Capillary Endothelial Cells In Vitro

Abstract

(1) The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (ECs). There are various cell types, in particular astrocytes, but also pericytes and neurons, located in close vicinity to the capillary ECs which may influence formation and function of the BBB. Based on this consideration, this paper discusses various aspects of the influence of the surrounding cells on brain capillary ECs with special focus on the role of astrocytes. (2) Based on the morphology of the BBB, important aspects of brain EC functions are summarized, such as transport functions and maintenance of low paracellular permeability. Moreover, various facets are discussed with respect to the influence of astrocytes, pericytes, microglia, and neurons on the BBB. Data on the role of glial cells in the ontogenesis of the BBB are presented subsequently. The knowledge on this subject is far from being complete, however, these data imply that the neural/neuronal environment rather than glial cells may be of importance in the maturation of the barrier. (3) The role of glial cells in the induction and maintenance of the BBB is discussed under physiological as well as pathological conditions. Although the literature presents manifold evidence for a great variety of effects induced by astroglia, there are also many controversies, which may result from different cellular models and experimental conditions used in the respective studies. Numerous factors secreted by astrocytes have been shown to induce a BBB phenotype. On the molecular level, increased expression of barrier-relevant proteins (e.g., tight junction proteins) is documented in the presence of astrocyte-derived factors, and many studies demonstrate the improvement of physiological parameters, such as increased transendothelial resistance and decreased paracellular permeability, in different in vitro models of the BBB. Moreover, one has to take into account that the interaction of brain ECs and astrocytes is bi-directional, and that the other cell types surrounding the brain microvasculature also contribute to BBB function or dysfunction, respectively. (4) In conclusion, it is expected that the present and future research focused on molecular mechanisms and signaling pathways will produce new and exciting insights into the complex network of BBB regulation: the cornerstone is laid.

Absence of Glial α-Dystrobrevin Causes Abnormalities of the Blood-Brain Barrier and Progressive Brain Edema

“…Transmission Electron Microscopy-Perfused brains were fixed in 4% paraformaldehyde and 15% saturated picric acid in 1ϫ PBS at 4°C for 24 h and postfixed in a mixture of 1% osmium tetroxide (OsO 4 ), 0.8% potassium ferricyanide K 4 [Fe(CN) 6 ], and the material was processed for transmission electron microscopy using standard protocols and analyzed in JEM 1011 (JEOL).…”

“…The astrocytic perivascular endfeet are closely apposed to the abluminal endothelial surface and are separated by but also cooperate in the formation and maintenance of the basement membrane composed of different extracellular matrix (ECM) proteins. Numerous observations indicate that both direct astrocyte interactions and astrocyte-derived factors are essential for the development and/or maintenance of BBB properties in BEC (2,6,7). However, our understanding of the exact molecules and mechanisms employed by astrocytes to influence BBB during ontogenic development and influence its maturation and permeability is far less comprehensive.…”

Nanoparticle transport across the blood brain barrier

“…Astrocytes release inductive signals that regulate the BBB 43 and play a role in maintaining water, ionic, and amino acid homeostasis within the CNS. 1 With an electrical resistance estimated to be 1500-2000 Vcm 2 , brain endothelium possesses a much higher electrical resistance than other systemic endothelia with 3-33 Vcm 2 17 further limiting diffusion of certain molecules across the BBB.…”

Pericytes from Brain Microvessels Strengthen the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells

“…Cells surrounding brain capillaries, such as astrocytes, pericytes, perivascular microglia, and neurons contribute to the formation and maintenance of a functional BBB in the central nervous system. Among these cells, astrocytes were the first to be recognized as regulators of brain endothelial characteristics and functions (for reviews see Abbott 2005;Abbott et al 2006;Haseloff et al 2005) including the induction of tight junctions (TJs) (Tao-Cheng et al 1987), a fundamental characteristic of the BBB. Brain pericytes, the cells sharing the basal membrane with capillary endothelial cells, were recently found to be also able to induce BBB functions in cultured brain endothelial cells (Hayashi et al 2004;Dohgu et al 2005).…”