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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.
AuthorsKyriaki Bakirtzi, Gail West, Claudio Fiocchi, Ivy Ka Man Law, Dimitrios Iliopoulos, Charalabos Pothoulakis
JournalThe American journal of pathology (Am J Pathol) Vol. 184 Issue 12 Pg. 3405-14 (Dec 2014) ISSN: 1525-2191 [Electronic] United States
PMID25307345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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