title: Inappropriate angiogenic response as a novel mechanism of duodenal ulceration and impaired healing.
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.
  
  
  OBJECTIVE
  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.
authors: Diagnostic & Molecular Medicine, VA Medical Center, Long Beach, CA 90822, USA.
authors: Xiaoming
authors: X
authors: Deng
authors: Ximing
authors: X
authors: Xiong
authors: Tetyana
authors: T
authors: Khomenko
authors: Zsuzsanna
authors: Z
authors: Sandor
authors: Klara
authors: K
authors: Osapay
authors: Ganna
authors: G
authors: Tolstanova
authors: Joseph
authors: J
authors: Shiloach
authors: Longchuan
authors: L
authors: Chen
authors: Judah
authors: J
authors: Folkman
authors: Sandor
authors: S
authors: Szabo
mesh_terms: D043168:Angiostatins / Q000378:metabolism*; D000818:Animals; D003543:Cysteamine / Q000009:adverse effects; D004195:Disease Models, Animal; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D043169:Endostatins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D009570:Nitriles / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D043169:Endostatins; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009570:Nitriles; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D003543:Cysteamine; D043168:Angiostatins; C005557:propionitrile; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9