Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats.
OBJECTIVE
Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation.


METHODS
PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials.


RESULTS
PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats.


CONCLUSIONS
This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Marc
M
Mejias
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Laura
L
Coch
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Annalisa
A
Berzigotti
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Ester
E
Garcia-Pras
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Javier
J
Gallego
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Jaime
J
Bosch
Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Mercedes
M
Fernandez
D000818:Animals; D001652:Bile Ducts; D005136:Eye Proteins / Q000502:physiology* / Q000627:therapeutic use*; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology* / Q000517:prevention & control*; D008026:Ligation; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000502:physiology* / Q000627:therapeutic use*; D017082:Portal Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000502:physiology* / Q000627:therapeutic use*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
Angiogenesis; Cirrhosis