Angiostatin inhibits experimental liver fibrosis in mice.
OBJECTIVE
Liver fibrosis is a response to chronic hepatic damage, which ultimately leads to liver failure and necessitates liver transplantation. A characteristic of fibrosis is pathological vessel growth. This type of angiogenesis may contribute to the disturbance of hepatocyte perfusion dynamics and lead to aggravation of disease. We hypothesized that angiostatin can inhibit pathological vessel growth and, consequently, the development of hepatic fibrosis.


METHODS
Hepatic fibrosis was induced by injection of carbon tetrachloride for 5 weeks. Angiostatin mice received carbon tetrachloride for 5 weeks and angiostatin during weeks 4 and 5. After 5 weeks, immunohistochemistry for endothelial cell marker von Willebrand factor and for cell proliferation was performed. Angiogenesis was quantified by counting the number of immunopositive microvessels. Also, the relative fibrotic surface was determined using Sirius Red histostaining and computer image analysis.


RESULTS
Immunohistochemistry revealed increased expression for von Willebrand factor in fibrotic livers. Immunopositive microvessels were localized in fibrotic areas surrounding larger vessels and in emerging fibrotic septa. Angiostatin reduced the number of immunopositive microvessels by 69% (p<0.001). In addition, angiostatin reduced the relative fibrotic area in the liver by 63+/-0.1% (p<0.001). Finally, angiostatin treatment was not associated with differences in cell proliferation.


CONCLUSIONS
Angiostatin inhibits the development of pathological angiogenesis and liver fibrosis in mice. These results warrant further evaluation of angiostatin as an antifibrotic agent, potentially contributing to the deferment of liver transplantation and reduced recurrence of fibrotic disease in the transplanted liver.
Vogten
J Mathys
JM
Department of Surgery, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands.
Drixler
Tamas A
TA
te Velde
Elisabeth A
EA
Schipper
Marguerite E
ME
van Vroonhoven
Theo J M V
TJ
Voest
Emile E
EE
Borel Rinkes
Inne H M
IH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D008099:Liver / Q000098:blood supply*; D008103:Liver Cirrhosis / Q000097:blood / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000032:analysis
D020533:Angiogenesis Inhibitors; D014841:von Willebrand Factor; D043168:Angiostatins