Original Paper

Angiogenesis

, Volume 17, Issue 3, pp 641-659

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

  • Daniela S. ArdeleanAffiliated withMolecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick ChildrenDivision of Rheumatology, The Hospital for Sick ChildrenDepartment of Immunology, University of Toronto
  • , Melissa YinAffiliated withBiological Sciences, Sunnybrook Health Sciences Center
  • , Mirjana JerkicAffiliated withMolecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick ChildrenHeart and Stroke Richard Lewar Centre of Excellence, University of Toronto
  • , Madonna PeterAffiliated withMolecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick ChildrenDepartment of Immunology, University of Toronto
  • , Bo NganAffiliated withDivision of Pathology, The Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , Robert S. KerbelAffiliated withBiological Sciences, Sunnybrook Health Sciences CenterDepartment of Medical Biophysics, University of Toronto
  • , F. Stuart FosterAffiliated withBiological Sciences, Sunnybrook Health Sciences CenterDepartment of Medical Biophysics, University of Toronto
  • , Michelle LetarteAffiliated withMolecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick ChildrenDepartment of Immunology, University of TorontoHeart and Stroke Richard Lewar Centre of Excellence, University of TorontoDepartment of Medical Biophysics, University of Toronto Email author 

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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

Endoglin VEGF Inflammation Angiogenesis Anti-VEGF therapy