gms | German Medical Science

67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12. - 15. Juni 2016, Frankfurt am Main

Endothelial angiopoietin-2 expression mediates cerebrovascular disintegration in Moyamoya disease

Meeting Abstract

  • Kinga G. Blecharz - Institut für Experimentelle Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Dietmar Frey - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Tobias Schenkel - Institut für Experimentelle Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Susanne M. Krug - Institut für Klinische Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Peter Vajkoczy - Institut für Experimentelle Neurochirurgie, Charité - Universitätsmedizin Berlin, Berlin, Germany; Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocP 091

doi: 10.3205/16dgnc466, urn:nbn:de:0183-16dgnc4667

Veröffentlicht: 8. Juni 2016

© 2016 Blecharz et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Previously, we have demonstrated that Moyamoya disease (MMD) serum, in contrast to serum from patients with the atherosclerotic cerebrovascular disease (ACVD) (control group), induced an overexpression and secretion of vascular-endothelial growth factor-A (VEGF-A), angiopoietin-2 and matrix metalloproteinase-9 (MMP-9) in cerebral ECs, while systemic concentrations of these cytokines in both patient groups did not differ. Moreover, MMD sera induced a down-regulation of cell-cell contacts accompanied by a loss of endothelial integrity. The aim of this study was to elucidate these effects in detail and understand the molecular mechanisms underlying the instability in MMD.

Method: By different electrophysiological, biochemical and functional assays the effects of MMD and ACVD serum in the presence or absence of inhibitors of the angiopoietin-2/tie-2 system and of the VEGF signaling pathway were tested on cerebral endothelial cells (ECs) in vitro. We used recombinant angiopoietin-1 (20 ng/ml), the VEGF antibody bevacizumab (250 µg/ml) and the pharmacological inhibitor of the VEGF-R2, SU5416 (25 µM) to block these pathways.

Results: The destabilizing effects on brain ECs in response to MMD serum were suppressed by inhibiting angiopoietin-2 rather than by blocking VEGF-A and its receptor VEGF-R2. Briefly, the permeability of the EC monolayer, which was lowered in response to MMD serum could be reconstituted by all three compounds reaching the baseline level of ACVD-treated cells. The expression of barrier tightening molecules claudin-5, occludin and VE-cadherin was improved by angiopoietin-2 but not by blockade of VEGF. In addition, the remarkable morphological changes induced by MMD serum could be attenuated either by inhibition of angiopoietin-2 or VEGF. Finally, the extracellular release of angiopoietin-2, MMP-9 and VEGF was lowered than by all substances MMD serum-incubated ECs. However, only VEGF could be reduced to the baseline level.

Conclusions: Our findings define brain ECs as the potential source of vessel destabilizing factors inducing the high plasticity state and disintegration of the cerebrovascular system in MMD in a paracrine manner. The inhibition of the vascular instability by pharmacological blockade of angiopietin-2 and VEGF may provide the basis for future preventive treatment strategies of MMD, and supports the understanding of the high incidence of cerebrovascular hemorrhagic and ischemic events in MMD.