Angiogenesis

, Volume 17, Issue 3, pp 641–659

Anti-VEGF therapy reduces intestinal inflammation in Endoglin heterozygous mice subjected to experimental colitis

Authors

  • Daniela S. Ardelean
    • Molecular Structure and Function Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick Children
    • Division of RheumatologyThe Hospital for Sick Children
    • Department of ImmunologyUniversity of Toronto
  • Melissa Yin
    • Biological SciencesSunnybrook Health Sciences Center
  • Mirjana Jerkic
    • Molecular Structure and Function Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick Children
    • Heart and Stroke Richard Lewar Centre of ExcellenceUniversity of Toronto
  • Madonna Peter
    • Molecular Structure and Function Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick Children
    • Department of ImmunologyUniversity of Toronto
  • Bo Ngan
    • Division of PathologyThe Hospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
  • Robert S. Kerbel
    • Biological SciencesSunnybrook Health Sciences Center
    • Department of Medical BiophysicsUniversity of Toronto
  • F. Stuart Foster
    • Biological SciencesSunnybrook Health Sciences Center
    • Department of Medical BiophysicsUniversity of Toronto
    • Molecular Structure and Function Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick Children
    • Department of ImmunologyUniversity of Toronto
    • Heart and Stroke Richard Lewar Centre of ExcellenceUniversity of Toronto
    • Department of Medical BiophysicsUniversity of Toronto
Original Paper

DOI: 10.1007/s10456-014-9421-x

Cite this article as:
Ardelean, D.S., Yin, M., Jerkic, M. et al. Angiogenesis (2014) 17: 641. doi:10.1007/s10456-014-9421-x

Abstract

Chronic intestinal inflammation is associated with pathological angiogenesis that further amplifies the inflammatory response. Vascular endothelial growth factor (VEGF), is a major angiogenic cytokine that has been implicated in chronic colitis and inflammatory bowel diseases. Endoglin (CD105), a transforming growth factor-β superfamily co-receptor expressed on endothelial and some myeloid cells, is a modulator of angiogenesis involved in wound healing and potentially in resolution of inflammation. We showed previously that Endoglin heterozygous (Eng+/−) mice subjected to dextran sodium sulfate developed severe colitis, abnormal colonic vessels and high tissue VEGF. We therefore tested in the current study if treatment with a monoclonal antibody to VEGF could ameliorate chronic colitis in Eng+/− mice. Tissue inflammation and microvessel density (MVD) were quantified on histological slides. Colonic wall thickness, microvascular hemodynamics and targeted MAdCAM-1+ inflamed vessels were assessed in vivo by ultrasound. Mediators of angiogenesis and inflammation were measured by Milliplex and ELISA assays. Colitic Eng+/− mice showed an increase in intestinal inflammation, MVD, colonic wall thickness, microvascular hemodynamics and the number of MAdCAM-1+ microvessels relative to colitic Eng+/+ mice; these parameters were all attenuated by anti-VEGF treatment. Of all factors up-regulated in the inflamed gut, granulocyte colony-stimulating factor (G-CSF) and amphiregulin were further increased in colitic Eng+/− versus Eng+/+ mice. Anti-VEGF therapy decreased tissue VEGF and inflammation-induced endoglin, IL-1β and G-CSF in colitic Eng+/− mice. Our results suggest that endoglin modulates intestinal angiogenic and inflammatory responses in colitis. Furthermore, contrast-enhanced ultrasound provides an excellent non-invasive imaging modality to monitor gut angiogenesis, inflammation and responses to anti-angiogenic treatment.

Keywords

EndoglinVEGFInflammationAngiogenesisAnti-VEGF therapy

Copyright information

© Springer Science+Business Media Dordrecht 2014