| First Author | Bakirtzi K | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 12 | Pages | 3405-14 |
| PubMed ID | 25307345 | Mgi Jnum | J:216582 |
| Mgi Id | MGI:5609066 | Doi | 10.1016/j.ajpath.2014.08.015 |
| Citation | Bakirtzi K, et al. (2014) The Neurotensin-HIF-1alpha-VEGFalpha Axis Orchestrates Hypoxia, Colonic Inflammation, and Intestinal Angiogenesis. Am J Pathol 184(12):3405-14 |
| abstractText | 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 VEGFalpha 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-1alpha and VEGFalpha 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. VEGFalpha 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-1alpha 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-1alpha-VEGFalpha axis in intestinal angiogenic responses and in the pathophysiology of colitis and inflammatory bowel disease. |
