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The neurotensin-HIF-1?-VEGF? axis orchestrates hypoxia, colonic inflammation, and
intestinal angiogenesis
#MMPMID25307345
Bakirtzi K
; West G
; Fiocchi C
; Law IK
; Iliopoulos D
; Pothoulakis C
Am J Pathol
2014[Dec]; 184
(12
): 3405-14
PMID25307345
show ga
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 VEGF? 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-1? and
VEGF? 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. VEGF? 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-1? 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-1?-VEGF? axis in intestinal angiogenic
responses and in the pathophysiology of colitis and inflammatory bowel disease.
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