Placental growth factor: New treatment target bringing hope for hepatopulmonary syndrome
Authors: Mercedes Fernandez
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. See Article On Page 634 Supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2014‐55473‐R), the European Union FEDER funds, the Scientific Foundation of the Spanish Association Against Cancer, and the Worldwide Cancer Research Foundation. The CIBERehd is an initiative from the Instituto de Salud Carlos III. Hepatopulmonary syndrome (HPS) has emerged as an important and relatively common clinical complication of cirrhosis and/or portal hypertension that occurs in up to 30% of patients with liver disease. It is characterized by impaired pulmonary arterial oxygenation due to pulmonary vascular dilatation and angiogenesis,1 which leads to debilitating, severe hypoxemia and a broader deterioration in quality of life.3 Patients with liver disease and HPS have an increased risk of death relative to patients with liver disease alone.1 HPS research is, therefore, of paramount importance to identify new therapeutic options. The study by Raevens and colleagues in this issue of hepatology4 not only improves our understanding of the pathophysiology of HPS but may also pave the way for new therapeutic strategies. This work reveals that excess pulmonary production of the proangiogenic placental growth factor (PlGF) is a pathogenetic hallmark of HPS that contributes to angiogenesis in the lung as HPS progresses. These findings significantly extend and strength the observations of several other research groups who have investigated the pathogenic role of pulmonary angiogenesis in HPS.1 Importantly, the authors have now shown that selective inhibition of the PlGF pathway, using a monoclonal antibody (αPIGF) that neutralizes murine PIGF, suppresses pathological angiogenesis and improves the pulmonary gas exchange abnormalities and development of hypoxemia that occur during HPS. These findings suggest that targeting therapy against PlGF may have real potential in the management of HPS. PlGF is a pleiotropic cytokine, belonging to the vascular endothelial growth factor (VEGF) family, that selectively binds to its membrane‐bound receptor VEGFR‐1 to stimulate angiogenesis.5 PlGF also enhances the activity of VEGF by competitively binding to VEGFR‐1 and displacing VEGF from VEGFR‐1, allowing VEGF to bind then to VEGFR‐2, which has stronger tyrosine kinase activity. PlGF also exerts its effects through other mechanisms such as intermolecular transphosphorylation of VEGFR‐2 following activation of VEGFR‐1, which amplifies the VEGFR‐2 response to VEGF binding.6 PlGF has attracted intense interest as a possible antiangiogenic therapeutic target because, unlike VEGF, its activity seems to be dispensable for physiologic angiogenesis and vascular maintenance in healthy adults, being specifically confined to pathological conditions.7 Consistently, the majority of normal mature tissues exhibit minimal endogenous PlGF expression, whereas PlGF is readily up‐regulated in various diseases, including tumor growth, ischemia, and chronic inflammation, in which PlGF contributes to the angiogenic switch that supports pathologic vascularization. Based on this knowledge, Raevens and colleagues put forth the hypothesis that inhibition of PlGF function might offer an attractive therapeutic option for HPS by selectively targeting pathological angiogenesis without affecting the growth or homeostasis of normal vessels, and, unlike VEGF/VEGFR inhibitors, it would therefore be likely to cause fewer side effects. The first key finding in support of this hypothesis was that common bile duct ligation (CBDL)–induced HPS in mice is associated with increased pulmonary expression of PlGF that correlates with the severity of the disease. The main cellular sources of this PlGF overproduction in the lung seem to be the type II alveolar epithelial cells and the lung macrophages that progressively accumulate after CBDL. Next, the authors demonstrated that treatment of mice with an anti‐PlGF neutralizing antibody reduced pulmonary angiogenesis and inflammation, improved endothelial function, and ameliorated the abnormal gas exchange and HPS progression after CBDL in both prophylactic and therapeutic treatment schedules. This important finding clearly defines a causal relationship between HPS pathogenesis and modulation of angiogenesis in the clinical manifestation of disease. Such evidence also gives credence to the theory that targeting this proangiogenic growth factor could correct the angiogenic imbalance in the setting of HPS, leading to prevention and even reversal of HPS progression. Furthermore, the study by Raevens et al. also clearly demonstrates that inhibition of PlGF not only inhibits pathological angiogenesis in HPS but also impairs the associated pulmonary macrophage infiltration and inflammation, leading to a general reduction of the pathological status. Raevens et al. have also dissected mechanisms by which the anti‐PlGF antibody exerts its beneficial effects in HPS. First, PIGF promotes pathological angiogenesis by stimulating endothelial cell growth and migration6 and acts as a survival factor for growing endothelial cells but not for quiescent vessels. Accordingly, Raevens et al. found that the anti‐PlGF antibody not only inhibits new vessel growth but also causes regression of the abnormally formed blood vessels. Second, the authors reported that the anti‐PlGF antibody is anti‐inflammatory and blocks the recruitment and accumulation of macrophages in lungs during HPS, consistent with the fact that PIGF chemoattracts VEGFR1‐positive angiocompetent macrophages.4 Interestingly, pulmonary macrophages in HPS could participate in angiogenesis by secreting angiogenic factors. Thus, by inhibiting their recruitment, the anti‐PlGF antibody could also inhibit new vessel growth. These findings highlight that regulators of angiogenesis can modulate the inflammatory response and the inflammatory response can modulate regulators of angiogenesis, which indicates that angiogenesis and inflammation are components of a common signaling pathway. One of the major problems in antiangiogenesis therapy is the propensity for neovascularized tissues to become resistant to treatments targeted against individual angiogenic factors by switching to compensatory production of other angiogenic molecules. However, the anti‐PlGF neutralizing monoclonal antibody used in the study by Raevens et al. did not cause any increase in VEGF or VEGFR1/2 levels, indicating minimal induction of an angiogenic escape program and further supporting that the anti‐PlGF antibody might represent an attractive tool in the therapy for angiogenesis‐dependent diseases such as HPS. In this regard, it should be noted that the same research team and collaborators have previously shown that blocking PlGF could be an effective strategy for reducing several complications of cirrhosis, such as fibrosis, inflammation, and portosystemic collateralization.9 Of course, another strength of the investigation by Raevens et al. is the establishment and characterization of a new experimental model of HPS induced by CBDL in mice, rather than in rats, which reproduces many features of human HPS disease and will be extremely useful to speed up the progress of research and enable the development of new drugs. Moving forward, it will be important from a translational point of view to determine whether this pathway and mechanisms are involved in human disease. Is PlGF up‐regulated and correlated with disease progression in patients with HPS? Which are the precise mechanisms that trigger pulmonary PlGF overproduction in HPS? Do the current results clearly define vascular angiogenesis as a major factor in human HPS? What is the potential crosstalk, if any, between PlGF and other mediators such as VEGF, nitric oxide, or carbon monoxide in the pathogenesis of HPS? Furher, it would be also interesting to determine whether increased levels of PlGF observed in HPS decrease after liver transplantation as HPS resolves. The setup by Raevens et al. of a new experimental mouse model of CBDL‐induced HPS could also be instrumental to identify the alterations unique to the CBDL model that drive the development of HPS (any role of bile duct proliferation?) and may unveil the susceptibility factors that result in an individual developing HPS. In summary, Raevens and colleagues have provided new and important insights about what happens in the pulmonary vasculature during HPS, as well as original experimental evidence concerning the capability of anti‐PlGF neutralizing antibodies to reduce pulmonary angiogenesis and signs of HPS in mice. These discoveries are encouraging and may offer new opportunities for treating HPS.Figure 1: PlGF in the pathophysiology of HPS. Pulmonary gas exchange between inhaled air and the blood occurs in the alveoli of the lungs. The one‐cell‐thick walls of the alveoli are composed of two distal airway epithelium cell types: type I squamous alveolar epithelial cells and type II great alveolar epithelial cells. The balloon‐shaped alveoli are surrounded by a fine network of blood capillaries that carry the CO2‐rich blood to the lungs to exchange for O2. In the pathological condition of HPS, there is increased production of PlGF by activated type II alveolar cells and by alveolar macrophages. PlGF then diffuses to adjacent pulmonary capillary endothelial cells, where it binds and activates VEGFR‐1. PlGF also further activates the VEGFR‐1‐expressing type II alveolar cells and stimulates the recruitment of VEGFR‐1‐positive macrophages. These alterations together trigger intrapulmonary angiogenesis, inflammation, and microvascular vasodilation, leading to defective oxygenation of blood in abnormal pulmonary capillaries and progressive hypoxemia. Author names in bold designate shared co‐first authorship.