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Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain

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Abstract

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.

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References

  • Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR (2009) VEGF-mediated disruption of endothelial CLN-5 promotes blood–brain barrier breakdown. Proc Natl Acad Sci U S A 106:1977–1982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561

    Article  CAS  PubMed  Google Scholar 

  • Batailler M, Droguerre M, Baroncini M, Fontaine C, Prevot V, Migaud M (2014) DCX-expressing cells in the vicinity of the hypothalamic neurogenic niche: a comparative study between mouse, sheep, and human tissues. J Comp Neurol 522:1966–1985

    Article  PubMed  Google Scholar 

  • Bauer H, Stelzhammer W, Fuchs R, Weiger TM, Danninger C, Probst G, Krizbai IA (1999) Astrocytes and neurons express the tight junction-specific protein occludin in vitro. Exp Cell Res 250:434–438

    Article  CAS  PubMed  Google Scholar 

  • Bennett L, Yang M, Enikolopov G, Iacovitti L (2009) Circumventricular organs: a novel site of neural stem cells in the adult brain. Mol Cell Neurosci 41:337–347

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Breier G, Breviario F, Caveda L, Berthier R, Schnürch H, Gotsch U, Vestweber D, Risau W, Dejana E (1996) Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system. Blood 87:630–641

    CAS  PubMed  Google Scholar 

  • Ciofi P, Garret M, Lapirot O, Lafon P, Loyens A, Prevot V, Levine JE (2009) Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus. Endocrinology 150:5509–5519

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Corada M, Zanetta L, Orsenigo F, Breviario F, Lampugnani MG, Bernasconi S, Liao F, Hicklin DJ, Bohlen P, Dejana E (2002) A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood 100:905–911

    Article  CAS  PubMed  Google Scholar 

  • Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Daneman R (2012) The blood–brain barrier in health and disease. Ann Neurol 2:648–672

    Article  Google Scholar 

  • Dellmann HD (1998) Structure of the subfornical organ: a review. Microsc Res Tech 41:85–97

    Article  CAS  PubMed  Google Scholar 

  • Duffy HS, John GR, Lee SC, Brosnan CF, Spray DC (2000) Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1beta in primary human fetal astrocytes. J Neurosci 20:Rc114

    CAS  PubMed  Google Scholar 

  • Engelhardt B (2003) Development of the blood–brain barrier. Cell Tissue Res 314:119–129

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt B, Conley FK, Butcher EC (1994) Cell adhesion molecules on vessels during inflammation in the mouse central nervous system. J Neuroimmunol 51:199–208

    Article  CAS  PubMed  Google Scholar 

  • Esser S, Lampugnani MG, Corada M, Dejana E, Risau W (1998) Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 111:1853–1865

    CAS  PubMed  Google Scholar 

  • Fanning AS, Ma TY, Anderson JM (2002) Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J 16:1835–1837

    CAS  PubMed  Google Scholar 

  • Faraci FM, Choi J, Baumbach GL, Mayhan WG, Heistad DD (1989) Microcirculation of the area postrema. Permeability and vascular responses. Circ Res 65:417–425

    Article  CAS  PubMed  Google Scholar 

  • 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) 232:14–26

    CAS  Google 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)

  • Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788

    Article  CAS  PubMed  Google Scholar 

  • Ganong WF (2000) Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 27:422–427

    Article  CAS  PubMed  Google Scholar 

  • Gotsch U, Borges E, Bosse R, Boggemeyer E, Simon M, Mossmann H, Vestweber D (1997) VE-cadherin antibody accelerates neutrophil recruitment in vivo. J Cell Sci 110:583–588

    CAS  PubMed  Google Scholar 

  • Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85:979–1000

    Article  CAS  PubMed  Google Scholar 

  • Hayashi N, Miyata S, Kariya Y, Takano R, Hara S, Kamei K (2004) Attenuation of glial scar formation in the injured rat brain by heparin oligosaccharides. Neurosci Res 49:19–27

    Article  CAS  PubMed  Google Scholar 

  • Howarth AG, Hughes MR, Stevenson BR (1992) Detection of the tight junction-associated protein ZO-1 in astrocytes and other nonepithelial cell types. Am J Physiol 262:C461–C469

    CAS  PubMed  Google Scholar 

  • Imamura Y, Morita S, Nakatani Y, Okada K, Ueshima S, Matsuo O, Miyata S (2010) Tissue plasminogen activator and plasminogen are critical for osmotic homeostasis by regulating vasopressin secretion. J Neurosci Res 88:1995–2006

    CAS  PubMed  Google Scholar 

  • Johnson AK, Gross PM (1993) Sensory circumventricular organs and brain homeostatic pathways. FASEB J 7:678–686

    CAS  PubMed  Google Scholar 

  • Kasten P, Schnoink G, Bergmann A, Papoutsi M, Buttler K, Rossler J, Weich HA, Wilting J (2007) Similarities and differences of human and experimental mouse lymphangiomas. Dev Dyn 236:2952–2961

    Article  PubMed  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 19:2465–2475

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koedel U, Winkler F, Angele B, Fontana A, Pfister HW (2002) Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 22:39-49

    Article  CAS  PubMed  Google Scholar 

  • Konig S, Hinard V, Arnaudeau S, Holzer N, Potter G, Bader CR, Bernheim L (2004) Membrane hyperpolarization triggers myogenin and myocyte enhancer factor-2 expression during human myoblast differentiation.J Biol Chem 279:28187-28196

    Article  CAS  PubMed  Google Scholar 

  • Langlet F, Mullier A, Bouret SG, Prevot V, Dehouck B (2013) Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. J Comp Neurol 521:3389–3405

    Article  PubMed Central  PubMed  Google Scholar 

  • Liebner S, Kniesel U, Kalbacher H, Wolburg H (2000) Correlation of tight junction morphology with the expression of tight junction proteins in blood–brain barrier endothelial cells. Eur J Cell Biol 79:707–717

    Article  CAS  PubMed  Google Scholar 

  • Mannari T, Morita S, Furube E, Tominaga M, Miyata S (2013) Astrocytic TRPV1 ion channels detect blood-borne signals in the sensory circumventricular organs of adult mouse brains. Glia 61:957–971

    Article  PubMed  Google Scholar 

  • Maolood N, Meister B (2009) Protein components of the blood–brain barrier (BBB) in the brainstem area postrema-nucleus tractus solitarius region. J Chem Neuroanat 37:182–195

    Article  CAS  PubMed  Google Scholar 

  • McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, Uschakov A, Oldfield BJ (2003) The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol 172:1–122

    Article  Google Scholar 

  • Miyata S, Morita S (2011) A new method for visualization of endothelial cells and extravascular leakage in adult mouse brain using fluorescein isothiocyanate. J Neurosci Methods 202:9–16

    Article  CAS  PubMed  Google Scholar 

  • Morita K, Sasaki H, Furuse M, Tsukita S (1999) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morita S, Miyata S (2012) Different vascular permeability between the sensory and secretory circumventricular organs of adult mouse brain. Cell Tissue Res 349:589–603

    Article  PubMed  Google Scholar 

  • Morita S, Miyata S (2013) Accessibility of low-molecular-mass molecules to the median eminence and arcuate hypothalamic nucleus of adult mouse. Cell Biochem Funct 31:668–677

    Article  CAS  PubMed  Google Scholar 

  • Morita S, Oohira A, Miyata S (2010) Activity-dependent remodeling of chondroitin sulfate proteoglycans extracellular matrix in the hypothalamo-neurohypophysial system. Neuroscience 166:1068–1082

    Article  CAS  PubMed  Google Scholar 

  • Morita S, Ukai S, Miyata S (2013) VEGF-dependent continuous angiogenesis in the median eminence of adult mice. Eur J Neurosci 37:508–518

    Article  CAS  PubMed  Google Scholar 

  • Morita S, Furube E, Mannari T, Okuda H, Tatsumi K, Wanaka A, Miyata S (2015) Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain. Cell Tissue Res 359:865–884

    Article  CAS  PubMed  Google Scholar 

  • Mullier A, Bouret SG, Prevot V, Dehouck B (2010) Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain. J Comp Neurol 518:943–962

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Niessen CM (2007) Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127:2525–2532

    Article  CAS  PubMed  Google Scholar 

  • Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Papadopoulos MC, Saadoun S, Woodrow CJ, Davies DC, Costa-Martins P, Moss RF, Krishna S, Bell BA (2001) Occludin expression in microvessels of neoplastic and non-neoplastic human brain. Neuropathol Appl Neurobiol 27:384–395

    Article  CAS  PubMed  Google Scholar 

  • Petrov T, Howarth AG, Krukoff TL, Stevenson BR (1994) Distribution of the tight junction-associated protein ZO-1 in circumventricular organs of the CNS. Mol Brain Res 21:235–246

    Article  CAS  PubMed  Google 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 4:2049

    Article  CAS  PubMed  Google Scholar 

  • Rossner S, Mehlhorn G, Schliebs R, Bigl V (2001) Increased neuronal and glial expression of protein kinase C isoforms in neocortex of transgenic Tg2576 mice with amyloid pathology.Eur J Neurosci 13:269–278

    CAS  PubMed  Google Scholar 

  • Sado Y, Kagawa M, Naito I, Ueki Y, Seki T, Momota R, Oohashi T, Ninomiya Y (1998) Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem 123:767–776

    Article  CAS  PubMed  Google Scholar 

  • Sisó S, Jeffrey M, González L (2010) Sensory circumventricular organs in health and disease. Acta Neuropathol 120:689–705

    Article  PubMed  Google 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 147:195–204

    Article  PubMed Central  PubMed  Google 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 145:1189–1198

  • Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA (1986) Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103:755–766

    Article  CAS  PubMed  Google Scholar 

  • Tétrault S, Chever O, Sik A, Amzica F (2008) Opening of the blood–brain barrier during isoflurane anaesthesia. Eur J Neurosci 28:1330–1341

    Article  PubMed  Google 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 10:171–180

  • Willis CL, Garwood CJ, Ray DE (2007) A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neuroscience 150:498–509

    Article  CAS  PubMed  Google 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 27:697–709

    Article  CAS  PubMed  Google 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 33:1104–1114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yao Y, Chen ZL, Norris EH, Strickland S (2014) Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 5:3413

    PubMed Central  PubMed  Google Scholar 

  • Zhong Y, Saitoh T, Minase T, Sawada N, Enomoto K, Mori M (1993) Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin and ZO-2. J Cell Biol 120:477-483

    Article  CAS  PubMed  Google Scholar 

  • Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12:723–738

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan

    Shoko Morita, Eriko Furube, Tetsuya Mannari & Seiji Miyata

  2. Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Shoko Morita, Hiroaki Okuda, Kouko Tatsumi & Akio Wanaka

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  1. Shoko Morita
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  2. Eriko Furube
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  3. Tetsuya Mannari
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  4. Hiroaki Okuda
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  5. Kouko Tatsumi
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  6. Akio Wanaka
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  7. Seiji Miyata
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Correspondence to Seiji Miyata.

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This work was supported in part by Scientific Research Grants from the Japan Society for the Promotion of Science (no. 24500411 to S. Miyata and no. 26830029 to S. Morita), the Salt Science Research Foundation (no. 1555 to S. Miyata) and a Sasakawa Scientific Research Grant from the Japan Science Society (no. 27–403 to E. Furube).

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Morita, S., Furube, E., Mannari, T. et al. Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain. Cell Tissue Res 363, 497–511 (2016). https://doi.org/10.1007/s00441-015-2207-7

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