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. 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. CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. The term inflammatory bowel disease (IBD) is used to describe two chronic and debilitating inflammatory disorders, namely, Crohn disease (CD) and ulcerative colitis. Although genetic and environmental factors and microbes are involved in the development of both diseases,1Sands B.E. Inflammatory bowel disease: past, present, and future.J Gastroenterol. 2007; 42: 16-25Crossref PubMed Scopus (195) Google Scholar the etiology of IBD still remains largely unclear. The neuropeptide neurotensin (NT), via its high-affinity receptor, NTR1, is an important mediator of intestinal inflammation.2Castagliuolo I. Wang C.C. Valenick L. Pasha A. Nikulasson S. Carraway R.E. Pothoulakis C. Neurotensin is a proinflammatory neuropeptide in colonic inflammation.J Clin Invest. 1999; 103: 843-849Crossref PubMed Scopus (117) Google Scholar, 3Koon H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar NT, a 13–amino acid neuropeptide initially isolated from bovine hypothalamus,4Carraway R. Leeman S.E. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami.J Biol Chem. 1973; 248: 6854-6861Abstract Full Text PDF PubMed Google Scholar is expressed in the brain and the intestine.5Uhl G.R. Goodman R.R. Snyder S.H. Neurotensin-containing cell bodies, fibers and nerve terminals in the brain stem of the rat: immunohistochemical mapping.Brain Res. 1979; 167: 77-91Crossref PubMed Scopus (245) Google Scholar In the intestine, NT is expressed in the endocrine N cells, localized in the intestinal mucosa.6Helmstaedter V. Feurle G.E. Forssmann W.G. Ultrastructural identification of a new cell type–the N-cell as the source of neurotensin in the gut mucosa.Cell Tissue Res. 1977; 184: 445-452PubMed Google Scholar Expression levels of NT and NTR1 are up-regulated in the inflamed colonic mucosa in animal models and IBD patients.2Castagliuolo I. Wang C.C. Valenick L. Pasha A. Nikulasson S. Carraway R.E. Pothoulakis C. Neurotensin is a proinflammatory neuropeptide in colonic inflammation.J Clin Invest. 1999; 103: 843-849Crossref PubMed Scopus (117) Google Scholar, 3Koon H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar, 7Brun P. Mastrotto C. Beggiao E. Stefani A. Barzon L. Sturniolo G.C. Palù G. Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing after chronic intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G621-G629Crossref PubMed Scopus (85) Google Scholar Moreover, evidence from our and other laboratories suggests that NT/NTR-1 signaling is implicated in the pathophysiology of colitis by mechanisms involving the regulation of gene expression of inflammation-associated genes.7Brun P. Mastrotto C. Beggiao E. Stefani A. Barzon L. Sturniolo G.C. Palù G. Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing after chronic intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G621-G629Crossref PubMed Scopus (85) Google Scholar, 8Bakirtzi K. Hatziapostolou M. Karagiannides I. Polytarchou C. Jaeger S. Iliopoulos D. Pothoulakis C. Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors.Gastroenterology. 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E. D. C. factor and in inflammatory bowel Clin PubMed Scopus Google Scholar HIF-1α is for C.C. The hypoxia-inducible factors for 1999; PubMed Scopus Google Scholar, K. L. of regulation of the hypoxia-inducible by the tumor PubMed Google Scholar as a of the and responses to induces the expression of a genetic angiogenic as vascular endothelial growth factor in and PubMed Scopus Google Scholar, R. I. M. S. D. D. M. Xu HIF-1 inflammatory responses to intestinal J Physiol Gastrointest Liver Physiol. PubMed Scopus Google Scholar by on the on their VEGFα is a growth factor involved in development as as endothelial cell and a in angiogenesis and A. H. endothelial growth factor and PubMed Scopus Google Scholar the regulation of HIF-1 is important for the of the at of intestinal and inflammation. are to HIF-1 in cell in K. E. and tumor stimulate of hypoxia-inducible 1999; PubMed Google Scholar, P. E. 1 induces hypoxia-inducible factor 1 in human and PubMed Scopus Google Scholar, HIF-1 expression in healing in inflammatory cells by J Physiol Physiol. Google Scholar increased signaling in mouse colon results in colitis in S. K. C. S.H. factor experimental colitis through an inflammatory signaling Full Text Full Text PDF PubMed Scopus Google Scholar is the of NT to angiogenesis and is no evidence of a for NT in responses in the intestinal NT and its in the in S. K. S. S. M. P. S. M. M. of activity and cell in vascular endothelial cells by a of Full Text Full Text PDF PubMed Scopus Google Scholar Moreover, cells tumor angiogenesis via an signaling S. K. cells tumor and through PubMed Scopus Google Scholar We hypothesized that NT/NTR1 signaling promotes HIF-1 transcriptional activity in the inflamed an in VEGFα expression, which a in intestinal manifestations of hypoxia and angiogenesis. We during mice have reduced angiogenesis. We that NT/NTR1 signaling in human induces HIF-1 activity in a diacylglycerol E. S. G. I. of diacylglycerol by hypoxia in the regulation of PubMed Scopus Google Scholar, S. A. A. I. for the of diacylglycerol in the activation of hypoxia-inducible factor 1 by Biol Chem. PubMed Scopus Google Scholar increased expression of its which in tube formation in human intestinal microvascular endothelial cells We for the to our that neuropeptide signaling regulate the effects of the factor an to angiogenesis. Our results demonstrate the importance of NTR1–HIF-1α–VEGFα interactions in the pathophysiology of colitis and the intestinal angiogenic We used the and NT HIF-1α VEGFα and growth factor The human neurotensin receptor 1 gene isolated from D. S. Pothoulakis C. expression in human Biol Chem. PubMed Scopus Google Scholar with and at the to were by of cells with a as L. D. and expression of the in with a Natl Acad Sci U S A. PubMed Scopus Google Scholar NCM460-NTR1 cells were as in colonic epithelial cells (NCM460-NTR1) were in with bovine and at in with cells were treated with 10−7 mol/L NT 6 in the of 10−7 VEGFα of with 10−7 mol/L NTR1 of with mol/L hours of with mol/L HIF-1α and nuclear using the nuclear isolation were isolated as K. 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Pothoulakis C. effects of receptor during colitis in of the growth factor J PubMed Scopus Google Scholar in to mice and by of were with of were to their and 48 hours colitis by that of NT a for colitis were 6 after colitis tissues were isolated and for from mouse human isolated using and using the for of using the to the tissues were in and in Tissue were by the Pathology were and with mouse at were with and were with an for development were the and using the as S. M. C. C. G. R. S. A. C. as a of inflammatory bowel disease Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. L. P. G. of angiogenesis in human an on the and of J Full Text PDF PubMed Scopus Google Scholar, for density and other PubMed Scopus Google Scholar tissues of mice were and with and were at of and in a with on a of to 6 for mucosal to for and to 1 for mucosal to a for M. A. 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K. cells tumor and through PubMed Scopus Google Scholar the of NT/NTR1 signaling in IBD with to compared the vascular density and mice after with using an that colonic angiogenesis increased in mice compared with that in mice cells at levels to and the increased angiogenic after of using an and increased cells in the colonic mucosa of mice and Moreover, of mice that mucosal integrity score in mice compared with that in mice increased in the colon of mice, with levels in mice, but the results did not results that NTR1 is important for colitis with from a using a colitis K. Karagiannides I. G. Pothoulakis C. The neurotensin promotes tumor development in a but not an inflammation-associated mouse of colon J PubMed Scopus Google Scholar and that is for angiogenesis. NT and its receptor, NTR1, are involved in intestinal and experimental I. Wang C.C. Valenick L. Pasha A. Nikulasson S. Carraway R.E. Pothoulakis C. Neurotensin is a proinflammatory neuropeptide in colonic inflammation.J Clin Invest. 1999; 103: 843-849Crossref PubMed Scopus (117) Google Scholar, 3Koon H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar, K. Karagiannides I. G. Pothoulakis C. The neurotensin promotes tumor development in a but not an inflammation-associated mouse of colon J PubMed Scopus Google Scholar The results in and that NT/NTR1 activation is involved in colitis-associated angiogenesis. VEGFα is a angiogenic factor angiogenesis and IBD S. M. V. G. E. A. A. A. S. C. S. angiogenesis and in inflammatory bowel disease 2009; Full Text Full Text PDF PubMed Scopus Google Scholar the of NTR1 signaling with VEGFα colonic epithelial cells NTR1 (NCM460-NTR1) were to 10−7 mol/L NT, and to VEGFα levels of We that VEGFα expression increased at 1 and 6 hours after NT and after and VEGFα levels were from We the of using and increased expression in NCM460-NTR1 cell after 1 and 6 hours of with 10−7 mol/L NT and results that NT/NTR1 signaling at both the transcriptional and the the in of VEGFα mRNA expression in NCM460-NTR1 cells, compared VEGFα mRNA levels and mice after of compared with colonic VEGFα mRNA levels were increased in to in mice mice no in VEGFα mRNA levels compared with and had VEGFα levels compared with mice the other the in in mouse compared with increased after of NT and that NT/NTR1 signaling has a in angiogenesis. as IBD is by metabolic shifts toward K. S. factor of intestinal factor during PubMed Scopus Google Scholar, S. cell Biol PubMed Scopus Google Scholar, S. manifestations and of the PubMed Scopus Google Scholar the a factor promoting VEGFα in and PubMed Scopus Google Scholar, R. I. M. S. D. D. M. Xu HIF-1 inflammatory responses to intestinal J Physiol Gastrointest Liver Physiol. PubMed Scopus Google Scholar is We hypothesized that the of VEGFα expression in NCM460-NTR1 cells after NT HIF-1α this NCM460-NTR1 cells were treated with 10−7 mol/L NT for 6 and cell were for mRNA and that HIF-1α levels were not increased after NT that HIF-1α in the 6 and for 6 and this NT cells were with the NTR1 and this a for In NCM460-NTR1 cells were treated with 10−7 mol/L NT for 1 were in and cell were at the Our results that the in HIF-1α levels as as after the of NT from the results that NT signaling HIF-1α in NCM460-NTR1 cells in an manner. We NT signaling promotes nuclear translocation, and transcriptional activity of on isolated and cell in NCM460-NTR1 cells with NT that NT promotes nuclear of HIF-1α and We assessed transcriptional activity of HIF-1 using an NCM460-NTR1 cells were with and and 48 hours cells were treated with 10−7 mol/L NT for 6 We that activity increased after 6 hours of NT that hypoxia results in the of the acid levels through the of the of E. S. G. I. of diacylglycerol by hypoxia in the regulation of PubMed Scopus Google Scholar, S. A. A. I. for the of diacylglycerol in the activation of hypoxia-inducible factor 1 by Biol Chem. PubMed Scopus Google Scholar We that of cells with mol/L activity in to NT that NT/NTR1 signaling promotes HIF-1α and transcriptional activity in a VEGFα expression to HIF-1α transcriptional NCM460-NTR1 cells with the HIF-1α Our results that of HIF-1α VEGFα expression NTR1 activation results in nuclear translocation, and transcriptional activity of to increased expression in a manner. We the of VEGFα expression in NCM460-NTR1 cells promotes angiogenesis in by tube formation of We NTR1 mRNA and that levels of NTR1 exposure of to 10−7 mol/L NT did not in increased tube formation cells were on exposure of the cells to growth factor in increased tube formation as a not In NT to cocultured with NCM460-NTR1 cells a in tube formation compared with to NT with NCM460-NTR1 cells in the of NT exposure and with the exposure of to 10−7 mol/L NT in the of 10−7 mol/L VEGFα this and results that NT angiogenesis in by promoting VEGFα expression in intestinal epithelial cells. have that the expression of the neuropeptide NT and its high-affinity receptor, NTR1, is in the colonic mucosa of animal models of intestinal and in colon from IBD patients.2Castagliuolo I. Wang C.C. Valenick L. Pasha A. Nikulasson S. Carraway R.E. Pothoulakis C. Neurotensin is a proinflammatory neuropeptide in colonic inflammation.J Clin Invest. 1999; 103: 843-849Crossref PubMed Scopus (117) Google Scholar, 3Koon H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar, 7Brun P. Mastrotto C. Beggiao E. Stefani A. Barzon L. Sturniolo G.C. Palù G. Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing after chronic intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G621-G629Crossref PubMed Scopus (85) Google Scholar We and that NT/NTR1 interactions intestinal of I. Wang C.C. Valenick L. Pasha A. Nikulasson S. Carraway R.E. Pothoulakis C. Neurotensin is a proinflammatory neuropeptide in colonic inflammation.J Clin Invest. 1999; 103: 843-849Crossref PubMed Scopus (117) Google Scholar, 3Koon H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar, 7Brun P. Mastrotto C. Beggiao E. Stefani A. Barzon L. Sturniolo G.C. Palù G. Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing after chronic intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G621-G629Crossref PubMed Scopus (85) Google Scholar, K. Karagiannides I. G. Pothoulakis C. The neurotensin promotes tumor development in a but not an inflammation-associated mouse of colon J PubMed Scopus Google Scholar compared with NTR1 have intestinal during colitis and that this is with reduced during colitis. Our in and in evidence that NT angiogenesis by increased expression of the factor VEGFα in which in stimulates tube formation by on We evidence that the of VEGFα activation in in to NT the activation of the factor This HIF-1α NT NT to not in our experimental our this is the to that NT regulates angiogenesis in the inflamed Our results that NT not tube formation to in the of NTR1 in cells. of NTR1 expression involved in this of results have activation of human colonic epithelial cells, which levels of NTR1, but increased and signaling in overexpressing this D. S. H. Pothoulakis C. Neurotensin stimulates expression in human colonic epithelial cells through J Physiol Physiol. PubMed Scopus Google Scholar, D. K. H. H.W. Pothoulakis C. growth receptor the inflammatory and responses of neurotensin in human colonic epithelial Biol Chem. PubMed Scopus Google Scholar, D. S. Pothoulakis C. expression in human Biol Chem. PubMed Scopus Google Scholar is increased expression of NTR1 in the colonic mucosa in colitis and IBD compared with levels of expression in H.W. Kim Y.S. Xu H. Kumar A. Zhao D. Karagiannides I. Dobner P.R. Pothoulakis C. Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis.Proc Natl Acad Sci U S A. 2009; 106: 8766-8771Crossref PubMed Scopus (55) Google Scholar, 7Brun P. Mastrotto C. Beggiao E. Stefani A. Barzon L. Sturniolo G.C. Palù G. Castagliuolo I. Neuropeptide neurotensin stimulates intestinal wound healing after chronic intestinal inflammation.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G621-G629Crossref PubMed Scopus (85) Google Scholar, M. Castagliuolo I. Wang C. M. E. Pothoulakis C. Neurotensin stimulates secretion in human colonic mucosa In of Full Text Full Text PDF PubMed Scopus Google Scholar have the that NT is involved in angiogenic S. K. S. S. M. P. S. M. M. of activity and cell in vascular endothelial cells by a of Full Text Full Text PDF PubMed Scopus Google Scholar, S. K. cells tumor and through PubMed Scopus Google Scholar The of an NT the of human endothelial cells and in the in S. K. S. S. M. P. S. M. M. of activity and cell in vascular endothelial cells by a of Full Text Full Text PDF PubMed Scopus Google Scholar Moreover, cells tumor angiogenesis in via an signaling S. K. cells tumor and through PubMed Scopus Google Scholar We in colonic epithelial cells, NT activates HIF-1α by a that stabilization, nuclear translocation, and transcriptional activity of of cells with the of NT/NTR1 signaling on HIF-1α transcriptional activity This suggests that HIF-1α activation in our is at in by involving the activation of a receptor and the of through the of E. 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PubMed Scopus Google Scholar in the of angiogenesis is a growth factor involved in development as as endothelial cell angiogenesis in the colon during active disease is a of IBD to a extent by VEGFα S. M. V. G. E. A. A. A. S. C. S. angiogenesis and in inflammatory bowel disease 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, M. in an of ulcerative effects of a PubMed Scopus Google Scholar which a for IBD G. Neurotensin activity is in the in Res. PubMed Scopus Google Scholar VEGFα expression is in the and colon of IBD S. M. V. G. E. A. A. A. S. C. S. angiogenesis and in inflammatory bowel disease 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, S. E. M. K. and in disease and ulcerative a of chronic intestinal inflammation.Am J Gastroenterol. Google Scholar Our results that NT of NCM460-NTR1 colonic epithelial cells with increased VEGFα mRNA and the in in VEGFα expression after in mice. The source of NT in this human colonic epithelial cells cells not NT mRNA not the of an signaling our results an important for NT in colitis-associated angiogenesis by an signaling that VEGFα expression We the and of the for with the and the Pathology at for colonic and were by and the and the of the signaling and to the and of the to experimental and authors in the and to the the
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