SESSION 11Blood brain -barrier

L.11.1Molecular mechanisms of immune cell migration across theblood–brain barrierBritta EngelhardtTheodor Kocher Institute, University of Bern, CH-3012 Bern, SwitzerlandE-mail address: bengel@tki.unibe.ch

Central nervous system (CNS) homeostasis is a prerequisite forproper electrical activity of neuronal cells. Therefore the endothelialblood–brain barrier (BBB) and the epithelial blood–cerebrospinalfluid barrier (BCSFB) tightly seal off the CNS from the continuouslychanging milieu within the blood stream. In spite of these barriersthe CNS is, however, subject to immune surveillance and immunemediated diseases. We have shown that in experimental autoimmuneencephalomyelitis (EAE) different sets of memory/effector T cells cancross the non-inflamed BBB or BCSFB using specific molecular keysand gain access to the cerebrospinal fluid (CSF) drained ventricular,subarachnoidal and perivascular spaces. When these pioneer T cellsencounter their specific antigen on antigen presenting cells strategi-cally localized immediately behind the brain barriers, reactivation ofthe T cells will trigger a local inflammatory response leading to thestimulation of the BBB. The activated BBB will then provide noveltraffic signals allowing for the entry of large numbers of circulatinginflammatory cells into the perivascular spaces and finally across theglia limitans into the CNS parenchyma where they cause tissue injury.

doi:10.1016/j.vph.2011.08.077

L.11.2Endothelial Wnt/β-catenin signaling reduces vascularization,barrier breakdown and tumor growth in a mouse glioma modelMarco Reisa, Cathrin J. Czupallaa, Nicole Zieglera, Kavi Devraja, SaschaSeidela, Rosario Heckb, Sonja Thoma, Jadranka Macasa, ErnestoBockampb, Stefanie Dimmelerc, Karl H. Platea, Stefan LiebneraaInstitute of Neurology (Edinger-Institute), Johann WolfgangGoethe-University Frankfurt Medical School, Heinrich-Hoffmann-Straβe7, 60528 Frankfurt, GermanybMedical Center of the Johannes Gutenberg-University Mainz, III,Division of Experimental and Translational Oncology, Obere ZahlbacherStr. 63, 55131 Mainz, GermanycInstitute for Cardiovascular Regeneration, Johann WolfgangGoethe-University Frankfurt Medical School, Theodor-Stern-Kai 7,60590 Frankfurt am Main, GermanyE-mail address: stefan.liebner@kgu.de (S. Liebner)

Endothelial Wnt/β-catenin signaling is necessary for develop-mental angiogenesis of the central nervous system and differentia-tion of the blood–brain barrier (BBB), but it seems to be inoperable inthe adult. In particular, its relevance for vascularization and barrieralterations in brain glioma is largely unknown.

To investigate the effect of Wnt/β-catenin signaling for braintumor angiogenesis, we generated mouse GL261 glioma cell linesexpressing either Wnt1 or the Wnt signaling inhibitor dickkopf-1(Dkk1) in a doxycycline-dependent manner.

We show that in subcutaneous and intracranial glioma, endothe-lial β-catenin stabilization by Wnt1 resulted in a more quiescentvessel phenotype and induced the attachment of mural cells.Accordingly, tumor vessels of Wnt1 expressing glioma were lesspermeable and showed distinct junctional staining of the tightjunction marker claudin-3. Conversely, Dkk1 increased vessel densityand promoted tumor growth. Wnt1 activated the Dll4/Notch pathway

in tumor endothelia, inhibiting an angiogenic and favoring aquiescent endothelial phenotype.

Currently,we investigate in detail the additional, evenmore complexeffects of the Wnt/ β-catenin pathway in endothelial cell biology.

In conclusion, physiological levels of Wnt/β-catenin signalingpromote angiogenesis, whereas sustained and reinforced signalingleads to inhibition of angiogenesis and vessel stabilization, whichmight proof to be a valuable therapeutic target for anti-angiogeniccancer therapy.

doi:10.1016/j.vph.2011.08.078

L.11.3Basement membranes of the blood vessel wall and theircontribution to structural and functional vascular integrityLydia SorokinPhysiological Chemistry and Pathobiochemistry; Münster University,Münster, GermanyE-mail address: sorokin@uni-muenster.de

Basement membrane (BM) composition varies with both bloodvessel and with tissue type. Of all BM components, the laminin familyshows the greatest variability and represents the biological activecomponent of BMs, interacting with a wide repertoire of integrin andnon-integrin receptors to control functions such as vessel integrityand permeability. I will focus on central nervous system (CNS)microvessels, which have a unique composition of cellular andextracellular matrix layers that collectively constitute the blood–brainbarrier. In addition to the endothelial cell monolayer and itsunderlying BM, cerebral microvessels are ensheathed by astrocyteendfeet and leptomeningeal cells, which contribute to a second BM,the so-called parenchymal BM as it delineates the border to the brainparenchyma. At the level of capillaries these two BMs fuse to form asingle structure, which shares characteristics of both endothelial andparenchymal BMs. While considerable information is available on thecellular constitutents of the CNS microvessels and their contributionto the BBB, little is known about the BM layers. Our work has shownthat endothelial and parenchymal BMs of CNS vessels are structurallyand functionally distinct, and has highlighted their importance in therestricted permeability characteristic of the CNS microvessels. Inparticular, laminin isoforms are heterogeneously localized along thelength of CNS microvessels and play an important role in definingsites of high and low penetrability by infiltrating cells, such asextravasating leukocytes during inflammation.1 Data will be pre-sented on the biochemical differences of BMs of CNS microvessels,and how vascular laminins provide cues that determine mechanismsof leukocyte penetration of CNS postcapillary venules.1

1. Wu, C., F. Ivars, P. Anderson, R. Hallmann, D. Vestweber, P. Nilsson, H.Robenek, K. Tryggvason, J. Song, E. Korpos, K. Loser, S. Beissert, E.Georges-Labouesse, & L.M. Sorokin. 2009. Nat Med. 15, 519–27.

doi:10.1016/j.vph.2011.08.079

O.11.1Defective vascular integrity upon KRIT1/ICAP-1 complex loss inCCM correlates with aberrant beta 1 integrin-dependentextracellular matrix remodelingEva Faurobert, Claire Rome, Gwénola Boulday, Justyna Lisowska,Sandra Manet, Marilyne Malbouyres, KeramidasMichelle Kéramidas,Daniel Bouvard, Elisabeth Tournier-Lasserve, Florence Ruggiero,Jean-Luc Coll, Corinne Albiges-Rizo

Abstracts332