8 Moreover, important questions arise not only to the class of angiogenic inhibitors that can be used successfully, but also with respect to the safety, especially considering potential application in patients with critically ill portal hypertension and cirrhosis. Many of the currently available multitargeted therapeutic strategies are associated with toxicities, thereby limiting their use in critically ill patients. Recent preclinical studies suggest that therapies targeting placental growth factor (PlGF) activity may possess such a safety profile.9, 10 PlGF is a member of the VEGF

family and a specific ligand for VEGFR1 that was originally discovered and isolated from the human placenta. The human transcript for PlGF generates four isoforms (PlGF-1 to −4), PlGF-2 being the only one present Obeticholic Acid mw in mice.11 Unlike SCH727965 mouse VEGF, PlGF plays a negligible role in physiological angiogenesis and is not required as a survival signal for the maintenance of quiescent vessels in healthy tissues. Furthermore, studies in transgenic mice revealed that the angiogenic activity of PlGF is restricted to pathological conditions.12, 13 In contrast to VEGF inhibitors, a monoclonal anti-PlGF antibody (αPlGF) has been shown to reduce pathological angiogenesis

in various spontaneous cancers and other disease models without affecting healthy blood vessels, resulting in no major side effects in mice and humans.9, 10, 14, 15 Based on the aforementioned considerations, PlGF might be an attractive therapeutic target for cirrhosis, but nearly nothing is known about its pathogenetic role in this disorder, nor its therapeutic potential. Here, we demonstrate that anti-PlGF antibody treatment might be considered as a novel potential therapy for cirrhosis due to its multiple mechanisms of action against angiogenesis, inflammation, and hepatic fibrosis. We also provide mechanistic insight into the fibrogenic role of PlGF by demonstrating its biological effect on HSCs. Importantly, all these results were obtained in the

absence of the adverse effects that are usually associated with antiangiogenic therapies based on VEGF blockade. αPlGF, Casein kinase 1 anti-PlGF antibody; αSMA, α-smooth muscle actin; αVEGFR, anti-VEGFR antibody; BrdU, bromodeoxyuridine; ERK, extracellular signal-regulated kinase; HSC, hepatic stellate cell; IgG1, immunoglobulin G1; mRNA, messenger RNA; PAS, periodic acid-Schiff; PDGFRA, platelet-derived growth factor receptor-α; PlGF, placental growth factor; RTK, tyrosine kinase receptor; RT-PCR, reverse-transcription polymerase chain reaction; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. All experiments were performed in 8-week-old male PlGF wild-type (PlGF+/+) mice (50% Sv129/50% Swiss), matched PlGF-knockout mice (PlGF−/−) of the same genetic background (Vesalius Research Center Leuven, Belgium), and male Wistar rats (Charles River, Saint Aubin les Elseuf, France).