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

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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.

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Acknowledgments

We thank Genentech for kindly providing the G6-31 anti-VEGF antibody; Dr. Wen-Rong Lie from EMD Millipore for the mouse angiogenesis/growth factor magnetic bead panel kit; Lily Morikawa and Napoleon Law from the Pathology Core Centre of the Modeling Human Disease Toronto Centre for Phenogenomics, Toronto, for help with the CD31 staining; Dr. Herman Yeger, for the use of the Olympus microscope; John Sun (VisualSonics, Toronto) for performing the pilot ultrasound measurements in colitic mice. We also thank the reviewers for their insightful comments. This work was supported by Grants from the Canadian Institute of Health Research (CIHR) (MOP-6247) and the Heart and Stroke Foundation of Canada (T5598) to ML, and from the Terry Fox Foundation, VisualSonics Inc. and CIHR (MOP–12164) to FSF. D. S. Ardelean received the CIHR/Canadian Association of Gastroenterology/Abbott fellowship award.

Conflicts of interest

Dr. Foster discloses that he is a consultant to VisualSonics Inc. The other authors declare no conflicts of interest.

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Authors and Affiliations

  1. Molecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada

    Daniela S. Ardelean, Mirjana Jerkic, Madonna Peter & Michelle Letarte

  2. Division of Rheumatology, The Hospital for Sick Children, Toronto, Canada

    Daniela S. Ardelean

  3. Department of Immunology, University of Toronto, Toronto, Canada

    Daniela S. Ardelean, Madonna Peter & Michelle Letarte

  4. Biological Sciences, Sunnybrook Health Sciences Center, Toronto, Canada

    Melissa Yin, Robert S. Kerbel & F. Stuart Foster

  5. Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada

    Mirjana Jerkic & Michelle Letarte

  6. Division of Pathology, The Hospital for Sick Children, Toronto, Canada

    Bo Ngan

  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    Bo Ngan

  8. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Robert S. Kerbel, F. Stuart Foster & Michelle Letarte

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  3. Mirjana Jerkic
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Correspondence to Michelle Letarte.

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Ardelean, D.S., Yin, M., Jerkic, M. et al. Anti-VEGF therapy reduces intestinal inflammation in Endoglin heterozygous mice subjected to experimental colitis. Angiogenesis 17, 641–659 (2014). https://doi.org/10.1007/s10456-014-9421-x

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