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.
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Authors | Kyriaki Bakirtzi, Gail West, Claudio Fiocchi, Ivy Ka Man Law, Dimitrios Iliopoulos, Charalabos Pothoulakis |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 184
Issue 12
Pg. 3405-14
(Dec 2014)
ISSN: 1525-2191 [Electronic] United States |
PMID | 25307345
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- HIF1A protein, human
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- Receptors, Neurotensin
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- neurotensin type 1 receptor
- vascular endothelial growth factor A, mouse
- Trinitrobenzenesulfonic Acid
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Topics |
- Animals
- Colitis
(pathology)
- Colon
(cytology, pathology)
- Disease Models, Animal
- Endothelial Cells
(cytology)
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Immunohistochemistry
- Inflammation
(metabolism)
- Inflammatory Bowel Diseases
(chemically induced, metabolism)
- Intestinal Mucosa
(metabolism)
- Intestines
(blood supply)
- Male
- Mice
- Microcirculation
- Neovascularization, Pathologic
- Receptors, Neurotensin
(metabolism)
- Trinitrobenzenesulfonic Acid
(chemistry)
- Up-Regulation
- Vascular Endothelial Growth Factor A
(metabolism)
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