Angiogenesis

, Volume 17, Issue 3, pp 641–659

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

  • Daniela S. Ardelean
  • Melissa Yin
  • Mirjana Jerkic
  • Madonna Peter
  • Bo Ngan
  • Robert S. Kerbel
  • F. Stuart Foster
  • Michelle Letarte
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

Authors and Affiliations

  • Daniela S. Ardelean
    • 1
    • 2
    • 3
  • Melissa Yin
    • 4
  • Mirjana Jerkic
    • 1
    • 5
  • Madonna Peter
    • 1
    • 3
  • Bo Ngan
    • 6
    • 7
  • Robert S. Kerbel
    • 4
    • 8
  • F. Stuart Foster
    • 4
    • 8
  • Michelle Letarte
    • 1
    • 3
    • 5
    • 8
  1. 1.Molecular Structure and Function Program, Peter Gilgan Centre for Research and LearningThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of RheumatologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of ImmunologyUniversity of TorontoTorontoCanada
  4. 4.Biological SciencesSunnybrook Health Sciences CenterTorontoCanada
  5. 5.Heart and Stroke Richard Lewar Centre of ExcellenceUniversity of TorontoTorontoCanada
  6. 6.Division of PathologyThe Hospital for Sick ChildrenTorontoCanada
  7. 7.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  8. 8.Department of Medical BiophysicsUniversity of TorontoTorontoCanada