title: Anti-VEGF therapy reduces intestinal inflammation in Endoglin heterozygous mice subjected to experimental colitis.
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.
authors: 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.
authors: Daniela S
authors: DS
authors: Ardelean
authors: Melissa
authors: M
authors: Yin
authors: Mirjana
authors: M
authors: Jerkic
authors: Madonna
authors: M
authors: Peter
authors: Bo
authors: B
authors: Ngan
authors: Robert S
authors: RS
authors: Kerbel
authors: F Stuart
authors: FS
authors: Foster
authors: Michelle
authors: M
authors: Letarte
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D000071063:Endoglin; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006579:Heterozygote; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000071063:Endoglin; C502004:Eng protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor