title: Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice.
abstract: 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.
  
  
  CONCLUSIONS
  PlGF is a disease-candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile.
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Van Steenkiste
authors.forename: Jordi
authors.initials: J
authors.lastname: Ribera
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.forename: Montse
authors.initials: M
authors.lastname: Pauta
authors.forename: Sònia
authors.initials: S
authors.lastname: Tugues
authors.forename: Christophe
authors.initials: C
authors.lastname: Casteleyn
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Kim
authors.initials: K
authors.lastname: Olievier
authors.forename: Ben
authors.initials: B
authors.lastname: Schroyen
authors.forename: Hendrik
authors.initials: H
authors.lastname: Reynaert
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.forename: Bram
authors.initials: B
authors.lastname: Blomme
authors.forename: Stephanie
authors.initials: S
authors.lastname: Coulon
authors.forename: Femke
authors.initials: F
authors.lastname: Heindryckx
authors.forename: Martine
authors.initials: M
authors.lastname: De Vos
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Stassen
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.forename: Jose
authors.initials: J
authors.lastname: Altamirano
authors.forename: Ramón
authors.initials: R
authors.lastname: Bataller
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
mesh_terms: D000818:Animals; D006505:Hepatitis / Q000188:drug therapy*; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy*; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
chemical_list: C000608036:PGF protein, human; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor