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Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing

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Abstract

Background

Despite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated.

Aims

After we found that duodenal ulcers did not heal despite increased levels of vascular endothelial growth factor (VEGF), we tested the hypothesis that an imbalance in angiogenic VEGF and anti-angiogenic endostatin and angiostatin might be important in the development and delayed healing of experimental duodenal ulcers.

Methods

Levels of VEGF, endostatin, and angiostatin, and the expression and activity of related matrix metalloproteinases (MMP) 2 and 9 were measured in scrapings of rat proximal duodenal mucosa in the early and late stages of chemically induced duodenal ulceration. Furthermore, animals were treated with recombinant endostatin and MMP 2 inhibitor to test the relationship between MMP2 and endostatin and their involvement in healing of experimental duodenal ulcers.

Results

A concurrent increase of duodenal VEGF, endostatin, and angiostatin was noted during duodenal ulceration. Endostatin treatment aggravated duodenal ulcer. Levels of MMP2, but not MMP9, were increased. Inhibition of MMP2 reduced levels of endostatin and angiostatin, and attenuated duodenal ulcers.

Conclusions

Increased levels of endostatin and angiostatin induced by MMP2 delayed healing of duodenal ulcers despite concurrently increased VEGF. Thus, an inappropriate angiogenic response or “angiogenic imbalance” may be an important new mechanism in ulcer development and impaired healing.

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Acknowledgments

This study was supported by a Department of Veterans Affairs, Veterans Health Administration Merit Review grant and by contributions from CPRC, Inc.

Conflict of interest

No conflicts of interest exist.

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Authors and Affiliations

  1. Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, Long Beach, CA, 90822, USA

    Xiaoming Deng, Ximing Xiong, Tetyana Khomenko, Klara Osapay, Ganna Tolstanova, Longchuan Chen & Sandor Szabo

  2. Department of Pathology, University of California-Irvine, Irvine, CA, 92697, USA

    Xiaoming Deng, Tetyana Khomenko & Ganna Tolstanova

  3. Medical Health Care Groups, VA Medical Center, 5901 E. 7th Street, Long Beach, CA, 90822, USA

    Zsuzsanna Sandor

  4. Department of Medicine, University of California-Irvine, Irvine, CA, 92697, USA

    Zsuzsanna Sandor

  5. Biotechnology Unit, NIDDK, NIH Bldg 14A, Room 173, Bethesda, MD, 20892, USA

    Joseph Shiloach

  6. Departments of Pediatric Surgery and Cell Biology, Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Judah Folkman

  7. Departments of Pathology and Pharmacology, University of California-Irvine, Irvine, CA, 92697, USA

    Sandor Szabo

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  1. Xiaoming Deng
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  8. Longchuan Chen
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  9. Judah Folkman
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  10. Sandor Szabo
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Correspondence to Sandor Szabo.

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Deng, X., Xiong, X., Khomenko, T. et al. Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing. Dig Dis Sci 56, 2792–2801 (2011). https://doi.org/10.1007/s10620-011-1753-4

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  • DOI: https://doi.org/10.1007/s10620-011-1753-4

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