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


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.


RESULTS
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.


CONCLUSIONS
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.
Diagnostic & Molecular Medicine, Health Care Group, VA Medical Center, Long Beach, CA, USA.
Ganna
G
Tolstanova
Xiaoming
X
Deng
Tetyana
T
Khomenko
Pallavi
P
Garg
Brankica
B
Paunovic
Longchuan
L
Chen
Shanthi V
SV
Sitaraman
Joseph
J
Shiloach
Sandor
S
Szabo
Zsuzsanna
Z
Sandor
D000818:Animals; D015153:Blotting, Western; D003093:Colitis, Ulcerative / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007460:Iodoacetamide / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology
D043169:Endostatins; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D016264:Dextran Sulfate; D020780:Matrix Metalloproteinase 9; D007460:Iodoacetamide