Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis.

Abstract

AIMS:

Vascular endothelial growth factor (VEGF) and pathologic angiogenesis have been demonstrated to play a pathogenic role in the development and progression of inflammatory bowel disease. Thus, we hypothesized that the potent anti-angiogenic factor endostatin might play a beneficial role in experimental ulcerative colitis (UC).

MAIN METHODS:

We used three animal models of UC: (1) induced by 6% iodoacetamide (IA) in rats, or (2) by 3% dextran sulfate sodium (DSS) in matrix metalloproteinase-9 (MMP-9) knockout (KO) and wild-type mice, and (3) interleukin-10 (IL-10) KO mice. Groups of MMP-9 KO mice with DSS-induced UC were treated with endostatin or water for 5days.

KEY FINDINGS:

We found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in both rat and mouse models of UC. A positive correlation between the levels of endostatin or VEGF and the sizes of colonic lesions was seen in IA-induced UC. The levels and activities of MMP-9 were also significantly increased during UC induced by IA and IL-10 KO. Deletion of MMP-9 decreased the levels of endostatin in both water- and DSS-treated MMP-9 KO mice. Treatment with endostatin significantly improved DSS-induced UC in MMP-9 KO mice.

SIGNIFICANCE:

1) Concomitantly increased endostatin is a defensive response to the increased VEGF in UC, 2) MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental UC, and 3) endostatin treatment plays a beneficial role in UC. Thus, anti-angiogenesis seems to be a new therapeutic option for UC.

• Authors: Ganna Tolstanova, Xiaoming Deng, Tetyana Khomenko, Pallavi Garg, Brankica Paunovic, Longchuan Chen, Shanthi V Sitaraman, Joseph Shiloach, Sandor Szabo, Zsuzsanna Sandor
• Journal: Life sciences (Life Sci) Vol. 88 Issue 1-2 Pg. 74-81 (Jan 03 2011) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 21047522 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

• Endostatins
• Platelet-Derived Growth Factor
• Vascular Endothelial Growth Factor A
• Dextran Sulfate
• Matrix Metalloproteinase 9
• Iodoacetamide

Topics

• Animals
• Blotting, Western
• Colitis, Ulcerative (etiology, metabolism, physiopathology)
• Colon (drug effects, metabolism, physiopathology)
• Dextran Sulfate (pharmacology)
• Disease Models, Animal
• Endostatins (pharmacology, physiology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Iodoacetamide (pharmacology)
• Matrix Metalloproteinase 9 (genetics, metabolism, physiology)
• Mice
• Mice, Knockout
• Platelet-Derived Growth Factor (metabolism, physiology)
• Rats
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (metabolism, physiology)