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VEGF??? isoform specific regulation of T-cell-dependent experimental colitis in mice.

ABSTRACT: Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell-mediated experimental colitis remains largely unknown.The CD4? CD45RB(high) T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z transgenic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF??? aptamer (Macugen), adenoviral VEGF???, and the VEGF Trap were used to evaluate pathological importance.VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF??? using a highly selective RNA aptamer significantly attenuated CD4? CD45RB(high) T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF??? overexpression significantly alter colitis pathology.VEGF??? is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF??? isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broad-scale inhibition of all VEGF-A isoforms was not therapeutically beneficial.

SUBMITTER: Chidlow JH

PROVIDER: S-EPMC4798237 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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VEGF₁₆₄ isoform specific regulation of T-cell-dependent experimental colitis in mice.

Chidlow John H JH Glawe John D JD Pattillo Christopher B CB Pardue Sibile S Zhang Songlin S Kevil Christopher G CG

Inflammatory bowel diseases 20101109 7

<h4>Background</h4>Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the path ...[more]

PMID: 21674706

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Project description:BackgroundThe spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs), plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state.ResultsUsing a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF₁₆₅-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia-dependent manner.ConclusionsIsoform-specific VEGF degradation provides a possible explanation for numerous examples of isoform specificity in VEGF patterning and examples of proteases relocation of VEGF upon release.

Dataset Information

VEGF??? isoform specific regulation of T-cell-dependent experimental colitis in mice.

Publications

VEGF₁₆₄ isoform specific regulation of T-cell-dependent experimental colitis in mice.

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