title: The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis.
abstract: The expression of neurotensin (NT) and its receptor (NTR1) is up-regulated in experimental colitis and inflammatory bowel disease; NT/NTR1 interactions regulate gut inflammation. During active inflammation, metabolic shifts toward hypoxia lead to the activation of hypoxia-inducible factor (HIF)-1, which enhances vascular endothelial growth factor (VEGF) expression, promoting angiogenesis. We hypothesized that NT/NTR1 signaling regulates intestinal manifestations of hypoxia and angiogenesis by promoting HIF-1 transcriptional activity and VEGFα expression in experimental colitis. We studied NTR1 signaling in colitis-associated angiogenesis using 2,4,6-trinitrobenzenesulfonic acid-treated wild-type and NTR1-knockout mice. The effects of NT on HIF-1α and VEGFα were assessed on human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1) and human intestinal microvascular-endothelial cells. NTR1-knockout mice had reduced microvascular density and mucosal integrity score compared with wild-type mice after 2,4,6-trinitrobenzenesulfonic acid treatment. VEGFα mRNA levels were increased in NCM460-NTR1 cells treated with 10(-7) mol/L NT, at 1 and 6 hours post-treatment. NT exposure in NCM460-NTR1 cells caused stabilization, nuclear translocation, and transcriptional activity of HIF-1α in a diacylglycerol kinase-dependent manner. NT did not stimulate tube formation in isolated human intestinal macrovascular endothelial cells but did so in human intestinal macrovascular endothelial cells cocultured with NCM460-NTR1 cells. Our results demonstrate the importance of an NTR1-HIF-1α-VEGFα axis in intestinal angiogenic responses and in the pathophysiology of colitis and inflammatory bowel disease.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Gail
authors.initials: G
authors.lastname: West
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
authors.forename: Ivy Ka Man
authors.initials: IK
authors.lastname: Law
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California. Electronic address: cpothoulakis@mdenet.ucla.edu.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D003092:Colitis / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D008297:Male; D051379:Mice; D008833:Microcirculation; D009389:Neovascularization, Pathologic; D018028:Receptors, Neurotensin / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000737:chemistry; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018028:Receptors, Neurotensin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C114036:neurotensin type 1 receptor; C467480:vascular endothelial growth factor A, mouse; D014302:Trinitrobenzenesulfonic Acid