VEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis

doi:10.1053/j.gastro.2008.09.064

Gastroenterology

Volume 136, Issue 2, February 2009, Pages 585-595.e5

https://doi.org/10.1053/j.gastro.2008.09.064 Get rights and content

Background & Aims

Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and might also have a role in inflammation and immunity. We examined whether VEGF-A signaling has a role in inflammatory bowel disease (IBD).

Methods

Expression levels of VEGF-A, and its receptors VEGFR-1 and VEGFR-2, were examined in samples from patients with IBD and compared with those of controls. The capacity of VEGF-A to induce angiogenesis was tested in human intestinal microvascular endothelial cells using cell-migration and matrigel tubule-formation assays. Levels of vascular cellular adhesion molecule-1 and intercellular adhesion molecule were measured by flow cytometry to determine induction of inflammation; neutrophil adhesion was also assayed. Expression patterns were determined in tissues from mice with dextran sulfate sodium (DSS)-induced colitis; the effects of VEGF-A overexpression and blockade were assessed in these mice by adenoviral transfer of VEGF-A and soluble VEGFR-1. Intestinal angiogenesis was measured by quantitative CD31 staining and leukocyte adhesion in vivo by intravital microscopy.

Results

Levels of VEGF-A and VEGFR-2 increased in samples from patients with IBD and colitic mice. VEGF-A induced angiogenesis of human intestinal microvascular endothelial cells in vitro as well as an inflammatory phenotype and adherence of neutrophils to intestinal endothelium. Overexpression of VEGF-A in mice with DSS-induced colitis worsened their condition, whereas overexpression of soluble VEGFR-1 had the opposite effect. Furthermore, overexpression of VEGF-A increased mucosal angiogenesis and stimulated leukocyte adhesion in vivo.

Conclusions

VEGF-A appears to be a novel mediator of IBD by promoting intestinal angiogenesis and inflammation. Agents that block VEGF-A signaling might reduce intestinal inflammation in patients with IBD.

Section snippets

Materials and Methods

For additional information on materials and methods, see supplementary materials and methods section (see supplementary materials and methods online at www.gastrojournal.org).

Mucosal and Plasma Levels of VEGF-A Are Up-Regulated in Patients With IBD

To compare the expression of VEGF-A under physiologic conditions and chronic inflammation, we first measured the levels of the VEGF-A protein in mucosal extracts from patients with active IBD and control individuals, using quantitative enzyme-linked immunosorbent assays (ELISA) of homogenized tissue samples (Figure 1A). The levels of VEGF-A in the mucosa of patients with either CD or UC were markedly (P < .05) enhanced compared with control individuals.

In addition, we also measured the levels

Discussion

It has now been clearly established that the microvascular changes associated with angiogenesis are key contributors to the tissue injury and remodeling process that inevitably accompanies chronic inflammation.10, 12, 14, 15 However, the important role played by angiogenesis in several chronic inflammatory diseases is still being elucidated.¹⁵ We and others have shown that intense angiogenesis occurs in humans with IBD in animals with experimental colitis.33, 34, 35

Increasing evidence suggests

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: F.S. and S.V. contributed equally to the paper.

: The authors disclose the following: Supported by grants from the Broad Medical Research Program, the “Premio SIGE UCB Post-Doc Award,” grants from A.I.R.C. and from the Italian Ministry of Health (Ricerca Finalizzata 2006, n.72) (to S.D.), and a grant from Ministerio de Ciencia e Innovación (SAF 2008-03676) (to M.S.).

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Basic—Alimentary TractVEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis

Background & Aims

Methods

Results

Conclusions

Section snippets

Materials and Methods

Mucosal and Plasma Levels of VEGF-A Are Up-Regulated in Patients With IBD

Discussion

Hum Pathol

Am J Pathol

Rheum Dis Clin North Am

FEBS letters

Gastroenterology

Am J Pathol

Dig Liver Dis

Gastroenterology

Gastroenterology

J Biol Chem

Gastroenterology

Blood

Blood

J Invest Dermatol

Blood

Etiopathogenesis of inflammatory bowel diseases

World J Gastroenterol

Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions

Am J Physiol

Unravelling the pathogenesis of inflammatory bowel disease

Nature

Inflammation and the mucosal microcirculation in inflammatory bowel disease: the ebb and flow

Curr Opin Gastroenterol

Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation

J Immunol

Angiogenesis in health and disease

Nat Med

Angiogenesis in life, disease and medicine

Nature

Angiogenesis in cancer, vascular, rheumatoid and other disease

Nat Med

Mechanisms of angiogenesis and arteriogenesis

Nat Med

Angiogenesis in inflammation

Autoimmun Rev

Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis

J Clin Invest

The codependence of angiogenesis and chronic inflammation

FASEB J

Cytokines and chemokines as regulators of angiogenesis in health and disease

Curr Pharm Des

Inflammation and cancer: the role of the immune response and angiogenesis

Cancer Treat Res

Basic—Alimentary Tract
VEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis