Neutralizing Anti-Vascular Endothelial Growth Factor (VEGF) Antibody Reduces Severity of Experimental Ulcerative Colitis in Rats: Direct Evidence for the Pathogenic Role of VEGF

Tolstanova, Ganna; Khomenko, Tetyana; Deng, Xiaoming; Chen, Longchuan; Tarnawski, Andrzej S.; Ahluwalia, Amrita; Szabó, Sándor; Sandor, Zsuzsanna

doi:10.1124/jpet.108.145128

Cited by 68 publications

(67 citation statements)

References 40 publications

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“…In rats, anti-VEGF antibody was investigated in colitis induced by iodoacetamide given intracolonically, and the results showed markedly less severe colitis as well as significant reductions in pro-inflammatory cytokines compared with controls. The beneficial effect of anti-VEGF antibody on colitis may be due to its moderating effects on vascular permeability and inflammatory cell recruitment [319]. Further studies showed that the levels of VEGF-A and VEGFR-2 were increased in patients with IBD as well as in DSS-treated mice.…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 93%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 93%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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“…Increased VEGF levels during early stages of UC may provide a mechanistic clue to impaired endothelial barrier and increased VP. In our previous study, we demonstrated that neutralizing anti-VEGF antibody diminished colonic VP and improved clinical and morphologic signs of IA-UC, 15 thus providing further support for the pathogenic role of increased VP in UC.…”

Section: Endothelial Damage In Ulcerative Colitismentioning

confidence: 99%

“…Other and our laboratories demonstrated activation of VEGF in UC, especially in its early phase, especially that neutralization of endogenous VEGF with specific anti-VEGF antibody abolishes increased endothelial microvascular permeability and prevents development of experimental UC. 15 In addition to elevated VEGF, other non-VEGF mechanisms such as activation of TLR2 by oxidation stress can contribute to increased endothelial microvascular permeability in UC. 44 TLR2 are present on some endothelial cells and TLR2 agonist increases endothelial monolayer permeability in vitro.…”

Section: Endothelial Damage In Ulcerative Colitismentioning

confidence: 99%

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Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Tolstanova

Deng

French

et al. 2012

Laboratory Investigation

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The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, Po0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both Po0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (Po0.05) and EP only in 4 days (Po0.05). Mucosal endothelial injury led to hypoxia (Po0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1a and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC. KEYWORDS: endothelial damage; epithelial permeability; hypoxia; inflammatory bowel disease; ulcerative colitis; vascular permeability Ulcerative colitis (UC) is characterized by chronic, recurrent ulcers and inflammation of the colonic mucosa. It has been postulated that impaired epithelial barrier function, resulting in penetration of bacteria and other antigens into the mucosa, is one of the major factors of UC pathogenesis.

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“…It will be of interest, therefore, to determine in the IBD setting whether ID1-expressing cells derived from the bone marrow reach the inflamed colon and whether these cells are of functional consequence in response to tissue injury. Although anti-VEGF therapy has been reported to ameliorate experimental colitis in association with reducing excessive vascular permeability, 46 it may also have the Figure 7 Id1 deletion in endothelial cells sensitizes mice to more severe colitis. Mice were given plain drinking water or 2.5% dextran sulfate sodium (w/v) for 7 days, followed by 14 days of plain drinking water.…”

Section: Discussionmentioning

confidence: 99%

Id1 Expression in Endothelial Cells of the Colon Is Required for Normal Response to Injury

Zhang

Subbaramaiah

Yantiss

et al. 2015

The American Journal of Pathology

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Inhibitor of DNA binding (ID)-1 is important for angiogenesis during embryogenesis and tumor development. Whether ID1 expression in endothelial cells of the colon is required for normal response to injury is unknown. We demonstrate that Id1 is up-regulated in colonic endothelial cells in an experimental model of colitis and in the inflamed mucosa of patients with inflammatory bowel disease. Because prostaglandin E 2 and tumor necrosis factor-a are also elevated in colitis, we determined whether these factors could induce ID1 transcription in cultured endothelial cells. Tumor necrosis factor-a stimulated ID1 transcription via early growth response 1 protein (Egr-1). By contrast, the induction of ID1 by prostaglandin E 2 was mediated by cAMP response elementebinding protein (CREB). To determine whether the increased ID1 levels in the endothelial cells of inflamed mucosa were an adaptive response that modulated the severity of tissue injury, Id1 was conditionally depleted in the endothelium of mice, which sensitized the mice to more severe chemical colitis, including more severe diarrhea, bleeding, and histological injury, and shorter colon compared with control mice. Moreover, depletion of Id1 in the vasculature was associated with increased CD31 þ aggregates and increased vascular permeability in inflamed mucosa compared with those in Id1 wild-type control mice. These results suggest that endothelial ID1 up-regulation in inflamed colonic mucosa is an adaptive response that modulates the severity of tissue injury. (Am J Pathol 2015 http://dx

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Neutralizing Anti-Vascular Endothelial Growth Factor (VEGF) Antibody Reduces Severity of Experimental Ulcerative Colitis in Rats: Direct Evidence for the Pathogenic Role of VEGF

Abstract: In

Cited by 68 publications

References 40 publications

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Id1 Expression in Endothelial Cells of the Colon Is Required for Normal Response to Injury

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