VEGF-A isoform modulation in an preclinical TNBS model of ulcerative colitis: protective effects of a VEGF164b therapy

Journal of Translational Medicine

J Michael Mathis²  J Steven Alexander³  Christopher G Kevil¹  James Traylor¹  Mihir Patel³  Chaitanya V Ganta³  Walter E Cromer² 

[1] Department of Pathology, LSU Health Sciences Center, Shreveport, LA, USA;Department of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, USA;Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA

关键词: Inflammation;    Colon;    TNBS;    Therapy;    Adenovirus;    Angiogenesis;    VEGF;    Ulcerative colitis;   

Others  :  826693
DOI  :  10.1186/1479-5876-11-207

 received in 2013-06-02, accepted in 2013-08-28,  发布年份 2013

【 摘 要 】

Background

Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the USA. A key component of UC is the increase in inflammatory angiogenesis of the colon during active disease. This increase is driven to a great extent by the over expression of VEGF-A. Recently, VEGF165_b (VEGF164_b in mouse), an anti-angiogenic form of VEGF-A was described and its regulation was determined to be disturbed in many pathologies such as cancer and pre-eclampsia.

Results

The aims of this study were to examine the role of this inhibitory VEGF by expressing this molecule in a model of intestinal inflammation, and to evaluate its expression as a potential new therapeutic approach for treating UC. A modified model of TNBS colitis was used to determine the effects of rVEGF164_b expression on colon inflammation. Expansion of the vascular system was assessed by immunhistochemical methods and macro- and microscopic measurements of inflammation in the colon were measured. Leukocyte invasion of the tissue was measured by myeloperoxidase assay and identification and counting of lymphoid follicles. Both angio- and lymphangiogenesis were reduced by expression of rVEGF164_b, which correlated with reduction in both gross and microscopic inflammatory scores. Leukocyte invasion of the tissue was also reduced by rVEGF164_b expression.

Conclusions

This is the first report using an endogenous inhibitory VEGF-A isoform for therapy in a model of experimental colitis. Inhibitory VEGF molecules play an important role in maintenance of gut homeostasis and may be dysregulated in UC. The results of this study suggest that restoration of rVEGF164_b expression has anti-inflammatory activity in a TNBS model and warrants further examination as a possible therapeutic for UC.

【 授权许可】

   
2013 Cromer et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Everhart JE, Ruhl CE: Burden of digestive diseases in the United States part II: lower gastrointestinal diseases. Gastroenterology 2009, 136:741-754.
• [2]Everhart JE, Ruhl CE: Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 2009, 136:376-386.
• [3]Irving PM, Gibson PR: Infections and IBD. Nat Clin Pract Gastroenterol Hepatol 2008, 5:18-27.
• [4]Irving PM, Shanahan F, Rampton DS: Drug interactions in inflammatory bowel disease. Am J Gastroenterol 2008, 103:207-219. quiz 206, 220
• [5]Karlen P, Lofberg R, Brostrom O, Leijonmarck CE, Hellers G, Persson PG: Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 1999, 94:1047-1052.
• [6]Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips MH, Pola R, Rutella S, Willis J, Gasbarrini A, Fiocchi C: Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology 2006, 130:2060-2073.
• [7]Deban L, Correale C, Vetrano S, Malesci A, Danese S: Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades. Am J Pathol 2008, 172:1457-1466.
• [8]Maconi G, Sampietro GM, Russo A, Bollani S, Cristaldi M, Parente F, Dottorini F, Bianchi Porro G: The vascularity of internal fistulae in Crohn's disease: an in vivo power Doppler ultrasonography assessment. Gut 2002, 50:496-500.
• [9]Scaldaferri F, Vetrano S, Sans M, Arena V, Straface G, Stigliano E, Repici A, Sturm A, Malesci A, Panes J, Yla-Herttuala S, Fiocchi C, Danese S: VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 2009, 136:585-595. e585
• [10]Bousvaros A, Leichtner A, Zurakowski D, Kwon J, Law T, Keough K, Fishman S: Elevated serum vascular endothelial growth factor in children and young adults with Crohn's disease. Dig Dis Sci 1999, 44:424-430.
• [11]Chidlow JH Jr, Langston W, Greer JJ, Ostanin D, Abdelbaqi M, Houghton J, Senthilkumar A, Shukla D, Mazar AP, Grisham MB, Kevil CG: Differential angiogenic regulation of experimental colitis. Am J Pathol 2006, 169:2014-2030.
• [12]Danese S, Sans M, Spencer DM, Beck I, Donate F, Plunkett ML, de la Motte C, Redline R, Shaw DE, Levine AD, Mazar AP, Fiocchi C: Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut 2007, 56:855-862.
• [13]Usui T, Ishida S, Yamashiro K, Kaji Y, Poulaki V, Moore J, Moore T, Amano S, Horikawa Y, Dartt D, Golding M, Shima DT, Adamis AP: VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest Ophthalmol Vis Sci 2004, 45:368-374.
• [14]Walter E, Cromer MHJ, Yoshinubo Odaka J, Michael Mathis J, Alexander S: Murine rVEGF164b, an inhibitory VEGF reduces VEGF-A dependent endothelial proliferation and barrier dysfunction. Microcirculation 2010, 17:537-547.
• [15]Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL: Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 1989, 96:795-803.
• [16]Gore RM: Colonic contour changes in chronic ulcerative colitis: reappraisal of some old concepts. AJR Am J Roentgenol 1992, 158:59-61.
• [17]Lorenz RG, Newberry RD: Isolated lymphoid follicles can function as sites for induction of mucosal immune responses. Ann N Y Acad Sci 2004, 1029:44-57.
• [18]Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO: Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 2008, 121:3487-3495.
• [19]Gavin TP, Wagner PD: Acute ethanol increases angiogenic growth factor gene expression in rat skeletal muscle. J Appl Physiol 2002, 92:1176-1182.
• [20]Ganta VC, Cromer W, Mills GL, Traylor J, Jennings M, Daley S, Clark B, Mathis JM, Bernas M, Boktor M, Jordan P, Witte M, Alexander JS: Angiopoietin-2 in experimental colitis. Inflamm Bowel Dis 2010, 16:1029-1039.
• [21]Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF: Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 2002, 196:1497-1506.
• [22]Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Manseau EJ, Dvorak AM, Dvorak HF: VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harb Symp Quant Biol 2002, 67:227-237.
• [23]Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D'Amore PA, Stein-Streilein J, Losordo DW, Streilein JW: Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005, 115:2363-2372.
• [24]Goebel S, Huang M, Davis WC, Jennings M, Siahaan TJ, Alexander JS, Kevil CG: VEGF-A stimulation of leukocyte adhesion to colonic microvascular endothelium: implications for inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2006, 290:G648-654.
• [25]Van Itallie CM, Fanning AS, Bridges A, Anderson JM: ZO-1 Stabilizes the Tight Junction Solute Barrier through Coupling to the Perijunctional Cytoskeleton. Mol Biol Cell 2009, 20:3930-3940.
• [26]Ambati BK, Patterson E, Jani P, Jenkins C, Higgins E, Singh N, Suthar T, Vira N, Smith K, Caldwell R: Soluble vascular endothelial growth factor receptor-1 contributes to the corneal antiangiogenic barrier. Br J Ophthalmol 2007, 91:505-508.
• [27]Davis JM, Ramakrishnan L: The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 2009, 136:37-49.
• [28]Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D'Amore PA, Dana MR, Wiegand SJ, Streilein JW: VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004, 113:1040-1050.
• [29]Sands BE, Kaplan GG: The role of TNFalpha in ulcerative colitis. J Clin Pharmacol 2007, 47:930-941.
• [30]Oshima T, Jordan P, Grisham MB, Alexander JS, Jennings M, Sasaki M, Manas K: TNF-alpha induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide. BMC Gastroenterol 2001, 1:5. BioMed Central Full Text
• [31]Deng X, Tolstanova G, Khomenko T, Chen L, Tarnawski A, Szabo S, Sandor Z: Mesalamine restores angiogenic balance in experimental ulcerative colitis by reducing expression of endostatin and angiostatin: novel molecular mechanism for therapeutic action of mesalamine. J Pharmacol Exp Ther 2009, 331:1071-1078.
• [32]Sandborn WJ, Targan SR: Biologic therapy of inflammatory bowel disease. Gastroenterology 2002, 122:1592-1608.
• [33]Siegmund B: Targeted therapies in inflammatory bowel disease. Dig Dis 2009, 27:465-469.