caa a22 4500 44579562X CHVBK 20180317145124.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s10620-011-1753-4 doi (NATIONALLICENCE)springer-10.1007/s10620-011-1753-4 Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing [Elektronische Daten] [Xiaoming Deng, Ximing Xiong, Tetyana Khomenko, Zsuzsanna Sandor, Klara Osapay, Ganna Tolstanova, Joseph Shiloach, Longchuan Chen, Judah Folkman, Sandor Szabo] 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. Springer Science+Business Media, LLC (Outside the USA), 2011 Duodenal ulcer nationallicence Angiogenic imbalance nationallicence VEGF nationallicence Endostatin nationallicence Angiostatin nationallicence MMP2 nationallicence TIMP-1 nationallicence Deng Xiaoming Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Xiong Ximing Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Khomenko Tetyana Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Sandor Zsuzsanna Medical Health Care Groups, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Osapay Klara Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Tolstanova Ganna Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Shiloach Joseph Biotechnology Unit, NIDDK, NIH Bldg 14A, Room 173, 20892, Bethesda, MD, USA aut Chen Longchuan Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Folkman Judah Departments of Pediatric Surgery and Cell Biology, Children's Hospital, Harvard Medical School, 02115, Boston, MA, USA aut Szabo Sandor Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/10(2011-10-01), 2792-2801 0163-2116 56:10<2792 2011 56 10620 https://doi.org/10.1007/s10620-011-1753-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-011-1753-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Deng Xiaoming Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Xiong Ximing Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Khomenko Tetyana Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Sandor Zsuzsanna Medical Health Care Groups, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Osapay Klara Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Tolstanova Ganna Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Shiloach Joseph Biotechnology Unit, NIDDK, NIH Bldg 14A, Room 173, 20892, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Chen Longchuan Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 700 1- Folkman Judah Departments of Pediatric Surgery and Cell Biology, Children's Hospital, Harvard Medical School, 02115, Boston, MA, USA aut NATIONALLICENCE 700 1- Szabo Sandor Diagnostic & Molecular Medicine, VA Medical Center, 5901 E. 7th Street, 90822, Long Beach, CA, USA aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/10(2011-10-01), 2792-2801 0163-2116 56:10<2792 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer