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Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice
Author(s) -
Van Steenkiste Christophe,
Ribera Jordi,
Geerts Anja,
Pauta Montse,
Tugues Sònia,
Casteleyn Christophe,
Libbrecht Louis,
Olievier Kim,
Schroyen Ben,
Reynaert Hendrik,
van Grunsven Leo A.,
Blomme Bram,
Coulon Stephanie,
Heindryckx Femke,
De Vos Martine,
Stassen Jean Marie,
Vinckier Stefan,
Altamirano Jose,
Bataller Ramón,
Carmeliet Peter,
Van Vlierberghe Hans,
Colle Isabelle,
MoralesRuiz Manuel
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24238
Subject(s) - portal hypertension , fibrosis , medicine , inflammation , placental growth factor , gastroenterology , cardiology , cirrhosis , vascular endothelial growth factor , vegf receptors
Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti‐PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti‐PlGF in liver cirrhosis. PlGF was significantly up‐regulated in the CCl 4 ‐induced rodent model of liver cirrhosis as well as in cirrhotic patients. Compared with wild‐type animals, cirrhotic PlGF −/− mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti‐PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal‐regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. Conclusion: PlGF is a disease‐candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile. (H EPATOLOGY 2011;)