Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain
- 865 Downloads
Fenestrated capillaries of the sensory circumventricular organs (CVOs), including the organum vasculosum of the lamina terminalis, the subfornical organ and the area postrema, lack completeness of the blood–brain barrier (BBB) to sense a variety of blood-derived molecules and to convey the information into other brain regions. We examine the vascular permeability of blood-derived molecules and the expression of tight-junction proteins in sensory CVOs. The present tracer assays revealed that blood-derived dextran 10 k (Dex10k) having a molecular weight (MW) of 10,000 remained in the perivascular space between the inner and outer basement membranes, but fluorescein isothiocyanate (FITC; MW: 389) and Dex3k (MW: 3000) diffused into the parenchyma. The vascular permeability of FITC was higher at central subdivisions than at distal subdivisions. Neither FITC nor Dex3k diffused beyond the dense network of glial fibrillar acidic protein (GFAP)-positive astrocytes/tanycytes. The expression of tight-junction proteins such as occludin, claudin-5 and zonula occludens-1 (ZO-1) was undetectable at the central subdivisions of the sensory CVOs but some was expressed at the distal subdivisions. Electron microscopic observation showed that capillaries were surrounded with numerous layers of astrocyte processes and dendrites. The expression of occludin and ZO-1 was also observed as puncta on GFAP-positive astrocytes/tanycytes of the sensory CVOs. Our study thus demonstrates the heterogeneity of vascular permeability and expression of tight-junction proteins and indicates that the outer basement membrane and dense astrocyte/tanycyte connection are possible alternative mechanisms for a diffusion barrier of blood-derived molecules, instead of the BBB.
KeywordsBlood–brain barrier Tight junction Vascular permeability Astrocyte Perivascular space Mouse
The hybridomas of anti-PV-1 (MECA-32) IgG developed by Dr. Eugene C Butcher and anti-ZO-1 IgG developed by Dr. Daniel A. Goodenough were obtained from the DSHB, which was developed under the auspices of the National Institute of Child Health and Human Development and is maintained by The University of Iowa, Iowa City, IA 52242, USA.
- Fry M, Hoyda TD, Ferguson AV (2007) Making sense of it: roles of the sensory circumventricular organs in feeding and regulation of energy homeostasis. Exp Biol Med (Maywood) 232:14–26Google Scholar
- Furube E, Morita M, Miyata S (2015) Characterization of neural stem cells and their progeny in the sensory circumventricular organs of adult mouse. Cell Tissue Res (in press)Google Scholar
- Katsuno T, Umeda K, Matsui T, Hata M, Tamura A, Itoh M, Takeuchi K, Fujimori T, Nabeshima Y, Noda T, Tsukita S, Tsukita S (2008) Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol Biol Cell 19:2465–2475CrossRefPubMedCentralPubMedGoogle Scholar
- Robins SC, Stewart I, McNay DE, Taylor V, Giachino C, Goetz M, Ninkovic J, Briancon N, Maratos-Flier E, Flier JS, Kokoeva MV, Placzek M (2013) α-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nat Commun 4:2049CrossRefPubMedGoogle Scholar
- Sonoda N, Furuse M, Sasaki H, Yonemura S, Katahira J, Horiguchi Y, Tsukita S (1999) Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 147:195–204CrossRefPubMedCentralPubMedGoogle Scholar
- Stan RV, Ghitescu L, Jacobson BS, Palade GE (1999) Isolation, cloning, and localization of rat PV-1, a novel endothelial caveolar protein. J Cell Biol 145:1189–1198Google Scholar
- Visser R, Beek JM van der, Havenith MG, Cleutjens JP, Bosman FT (1986) Immunocytochemical detection of basement membrane antigens in the histopathological evaluation of laryngeal dysplasia and neoplasia. Histopathology 10:171–180Google Scholar
- Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709CrossRefPubMedGoogle Scholar
- Yang Y, Thompson JF, Taheri S, Salayandia VM, McAvoy TA, Hill JW, Yang Y, Estrada EY, Rosenberg GA (2013) Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. J Cereb Blood Flow Metab 33:1104–1114CrossRefPubMedCentralPubMedGoogle Scholar