Abstract
The blood–brain barrier (BBB) is fundamental in maintaining central nervous system (CNS) homeostasis by regulating the chemical environment of the underlying brain parenchyma. Brain endothelial cells (BECs) constitute the anatomical and functional basis of the BBB. Communication between adjacent BECs is critical for establishing BBB integrity, and knowledge of its nanoscopic landscape will contribute to our understanding of how juxtaposed zones of tight-junction protein interactions between BECs are aligned. The review discusses and critiques types of nanostructures contributing to the process of BBB genesis. We further critically evaluate earlier findings in light of novel high-resolution electron microscopy descriptions of nanoscopic tubules. One such phenotypic structure is BEC cytoplasmic projections, which, early in the literature, is postulated as brain capillary endothelial cilia, and is evaluated and compared to the recently discovered nanotubules (NTs) formed in the paracellular spaces between BECs during barrier-genesis. The review attempts to elucidate a myriad of unique topographical ultrastructures that have been reported to be associated with the development of the BBB, viz., structures ranging from cilia to BEC tunneling nanotubules (TUNTs) and BEC tethering nanotubules (TENTs).
Highlights
The capillaries of the brain are special, as they are not conduits for blood, but are primarily responsible for ensuring that the neurons function in a strictly regulated homeostatic interstitium
The ability to monitor and study the orientation and alignment of brain endothelial cells (BECs) during barrier establishment is limited due to the lack of qualitative, three-dimensional, nanoscopic data. These limitations have engendered the theoretical premise that the barrier-genesis of brain capillary endothelial cells (ECs) is mainly determined by paracellular interaction demarcated by the presence of intercellular tight junctions (TJs): occludin, claudin-5, junctional adhesion molecules, desmosomes and gap junctions, all of which make up the junctional complex [1] and are known to be directly linked to the BEC actin cytoskeleton via the zonula occludens-1 plaque protein [1–3]
We address the schism between the high-resolution scanning electron microscopy (HR-SEM)-based evidence of endothelial NT generation observed during EC monolayer development, which provided insight into the development of the brain capillary, and compare this evidence to the immunofluorescence and molecular evidence underpinning the postulate for BEC “cilia”
Summary
The capillaries of the brain are special, as they are not conduits for blood, but are primarily responsible for ensuring that the neurons function in a strictly regulated homeostatic interstitium. The ability to monitor and study the orientation and alignment of brain endothelial cells (BECs) during barrier establishment is limited due to the lack of qualitative, three-dimensional, nanoscopic data. These limitations have engendered the theoretical premise that the barrier-genesis of brain capillary endothelial cells (ECs) is mainly determined by paracellular interaction demarcated by the presence of intercellular tight junctions (TJs): occludin, claudin-5, junctional adhesion molecules, desmosomes and gap junctions, all of which make up the junctional complex [1] and are known to be directly linked to the BEC actin cytoskeleton via the zonula occludens-1 plaque protein [1–3].
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