Role of placental growth factor in mesenteric neoangiogenesis in a mouse model of portal hypertension.
OBJECTIVE
Portal hypertension is responsible for the major complications associated with cirrhosis. Angiogenesis has been associated with the pathophysiology of portal hypertension. We investigated the role of placental growth factor (PlGF) and tested the effects of monoclonal antibodies against PlGF (alphaPlGF) in a mouse model of portal hypertension.


METHODS
Using a mouse model of prehepatic portal hypertension, we measured PlGF levels in the mesenteric tissue at different time points. We used knockout mice and alphaPlGF to determine the role of PlGF in the splanchnic hyperdynamic system and portosystemic collateral formation, examining its effects before and after portal hypertension was induced.


RESULTS
PlGF was significantly up-regulated in the mesenteric tissue of mice with portal hypertension. Compared with wild-type animals, the vascular density in the mesentery was reduced in PlGF knockout hypertensive mice, preventing collateral formation and attenuation of mesenteric artery flow without affecting portal pressure. In the prevention study, alphaPlGF showed similar findings as in the knockout study. In mice with portal hypertension, administration of alphaPlGF resulted in a 32% decrease in portal pressure, compared with mice given immunoglobulin G(1) (control).


CONCLUSIONS
Pathologic angiogenesis in the mesenteric tissues of mice with portal hypertension is mediated by PlGF. Blocking PlGF could be an effective strategy for reducing collateral formation and lowering portal pressure; further research into the effects in cirrhosis is warranted.
Van Steenkiste
Christophe
C
Faculty of Medicine and Health Sciences, Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
Geerts
Anja
A
Vanheule
Eline
E
Van Vlierberghe
Hans
H
De Vos
Filip
F
Olievier
Kim
K
Casteleyn
Christophe
C
Laukens
Debby
D
De Vos
Martine
M
Stassen
Jean-Marie
JM
Carmeliet
Peter
P
Colle
Isabelle
I
D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D003097:Collateral Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D008643:Mesentery / Q000098:blood supply* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D000072483:Placenta Growth Factor; D017082:Portal Pressure; D011257:Pregnancy Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013152:Splanchnic Circulation / Q000187:drug effects; D015854:Up-Regulation
D042501:Angiogenic Proteins; D000911:Antibodies, Monoclonal; D000959:Antihypertensive Agents; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor