Vessel Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 361

Tight junctions are composed of several transmembrane proteins, especially
occludin and claudins. Occludin extracellular domains span intercellular cleft.
Their intracellular domains connect the cell membrane to the cytoskeleton by
association with zonula occludens proteins (ZO1-ZO3) of the MAGUK family.
Claudin extracellular loops form the primary seals of tight junctions. Occludins
and claudins assemble into heteropolymers to form intramembranous strands along
endothelial cell contacts that allow regulation of selective diffusion of ions and
hydrophilic molecules. Extracellular loops of these heteropolymers interact with
junctional adhesion molecules. Claudin-1, -3, -5, and -12 contribute to the high
transport resistance of the brain tight junctions. Junctional adhesion molecules
(JAM1-JAM3) maintain tight junctions.
AdaptorsZO1toZO3,Ca 2 + -dependent protein Ser/Thr kinase, membrane-
associated guanylate kinase inverted proteins MAGI1 to MAGI3, multi-PDZ
domain-containing

protein-1, partitioning defective proteins Par3 and Par6

participate in the cytoplasmic plaques associated with tight junctions.
The cytoplasmic plaque is associated with another proteic complex of regulatory
and signaling molecules, small GTPases, regulator of G-protein signaling RGS5,
ZO1-associated nucleic acid-binding protein, junction-associated coiled-coil pro-
teins, etc.
Brain endothelial cells produce specific proteins, 20 such as solute carrier fam-
ily 35 member SLC35f2, adpribosylation factor-like ARL5b, transforming growth
factor- 1-stimulated clone 22 (TSC22) domain family member TSC22D1, 21 in-

tegral membrane protein ITM2a, 22 and epithelial membrane protein EMP1. 23
Epithelial membrane protein-1 colocalizes with occludin. This BBB tight junction-
associated protein is particularly expressed during cerebral ischemia [ 674 ]. 24

β

7.4.2 Neurovascular Units

Continuous capillaries with transport systems for nutrients and wastes are charac-
terized by: (1) between-endothelial cell tight junctions that occlude the intercellular

20 Blood-brain barrier control proteins, such as glucose transporter, P-glycoprotein, and transferrin
receptor, disappear in cultured endothelial cells that undergo dedifferentiation.
21 Member 1 of the TSC22 domain-containing family (TSC22D), also called transforming growth
factor- 1I4, is a tumor suppressor and transcriptional repressor of C-type

natriuretic peptide promoter. This transcription factor belongs to the family of early response gene
products. It homo- and heterodimerizes with TSC22D4 protein.
22 Integral transmembrane protein ITM2a is involved in T-cell activation and thymocyte develop-
ment.
23 Epithelial membrane proteins EMP1 to EMP3 belong to the peripheral myelin protein PMP22
gene family. In epithelia, PMP22 is coexpressed with occludin and ZO1 in or near tight junctions.
Protein EMP2 regulates surface expression of

β 1-induced protein TGF β

α V β 3 -integrins, caveolins, and glycosylphosphatidyl
inositol-anchored proteins, hence modulating cell-matrix and between-cell adhesions.
24 In cerebral ischemia model, BBB disruption occurs 1 to 24 h after reperfusion due to changes in
ion and nutrient transport, inflammation, and vascular remodeling.