Portal hypertension (PHT) is a heterogeneous clinical entity which develops in patients
with cirrhosis. It is responsible for many of the complications that occur in cirrhosis,
including gastroesophageal varices, hepatorenal syndrome, ascites, hepatic encephalopathy
and hypersplenism.1 There are three principal factors responsible for the development
of PHT, namely (1) purely mechanical obstruction resulting from hepatic fibrosis and
regenerative nodules; (2) contraction of sinusoidal and perisinusoidal contractile
cells due to an imbalance between intrahepatic vasoconstrictory and vasodilatory mediators
and (3) splanchnic vasodilation and increased portal blood flow.1 Factors leading
to the development of PHT include hypoxia, oxidative stress, inflammation and shear
stress as potential mediators for the angiogenic response. Vascular Endothelial Growth
factor (VEGF) is a key mediator in regulating the angiogenic switch in many pathological
conditions, and is also probably a major player in the neoangiogenic process during
the development of a hyperdynamic splanchnic circulation, and the formation of portal-systemic
collateral vessels.2 This has led to many studies seeking to identify signalling pathways
that interact with, or affect the formation and action of VEGF switching.
Mejias reports in this issue3 a new mechanism and therapeutic effect by targeting
endogenous pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive
rats. PEDF belongs to the subgroup of the so-called non-inhibitory serpins that lack
the protease inhibitory activity but which interacts with a variety of cellular components
and signalling cascades. For this reason, PEDF is best characterised as a multifunctional
protein with therapeutic effects in many diseases.4
5
The authors demonstrated that by employing an adenoviral-mediated gene transfer of
PEDF, which enhanced the expression of PEDF, only resulted in inhibition of neoangiogenesis.
This is important, since any drug used to treat or prevent PHT should ideally inhibit
neoangiogenesis without affecting the normal vessels. Moreover, in this experimental
approach, by applying prevention trials and intervention trials, authors showed to
diminish (1) significantly liver fibrosis by upregulation of matrix metalloproteinase-2
(MMP-2), (2) portosystemic collateralisation and (3) portal pressure in bile duct-ligated
rats. To translate these data to man, the authors investigated PEDF localisation in
HCV-related cirrhosis, and observed that PEDF was predominantly overexpressed in regenerative
micronodules, at the interface between liver parenchyma and highly neovascularised
fibrous septa. These PEDF-positive regions also correlated with high expression levels
of VEGF. This observation was further substantiated with in vivo data where the authors
showed a spatio-temporal PEDF expression that followed the upregulation of VEGF in
bile duct ligation (BDL)-ligated rats, CCl4-induced cirrhotic livers, and during neoangiogenesis
in the mesentery. Thus, this observation demonstrates an important element in underlying
the mechanism of PEDF therapy to counteract VEGF-related actions during neoangiogenesis.
Of note, in the BDL experimental model, PEDF was particularly effective when administered
during the early phase of liver disease (prevention trial), consistent with its capability
to interfere, in the liver, with the fibrogenesis/angiogenesis couple and, in the
mesentery, with the neovascular response at the time of its maximal expression (see
figure 1). These data indicate that, if translated into clinical usage, such drugs
would interfere with neoangiogenesis at an early stage of PHT.
At present, we have various drugs that target almost exclusively the splanchnic and
intrahepatic vascular tone and which are used clinically to treat the complications
of PHT. However, there are two major unmet clinical needs: namely to halt or prevent
the rise of portal pressure before clinically significant PHT develops, and to increase
efficacy, once PHT has developed, with new therapeutic targets. With regard to the
first point, longitudinal studies in cirrhotic patients with baseline haemodynamic
assessment have clearly demonstrated that all PHT complications do not develop until
the hepatic venous pressure gradient (HVPG) exceeds 10 mm Hg, namely the range of
clinically significant PHT.6 Therefore, a drug which is able to prevent an increase
of portal pressure from the subclinical to the clinically significant range would
prevent many of the sequelae we observe.
Figure 1
Pigment epithelium-derived factor (PEDF) gene transfer as a novel therapeutic agent.
PEDF is overexpressed in the liver and mesenteric vascular bed in animal models of
portal hypertension and cirrhosis. PEDF and vascular endothelial growth factor (VEGF)
are unidirectionally upregulated and correlate with mesenteric neovascularisation
and liver fibrogenesis during cirrhosis. In vivo PEDF gene transfer mediated by adenoviral
vectors (AdPEDF) effectively suppresses mesenteric pathological angiogenesis and intrahepatic
fibrogenesis in bile duct ligation (BDL) rats, leading to a significant decrease in
portal pressure.
Since neoangiogenesis actively contributes to PHT from the first steps of its development,1
drugs with antiangiogenic properties are attractive candidates to prevent PHT.7 However,
the development of clinical studies to investigate this has been hampered by drug
toxicity and the concerns about interfering with physiological angiogenesis.7 The
results presented by Mejias launches PEDF as a promising agent with the potential
ability to affect portal pressure by specifically targeting pathological angiogenesis.
Conversely, the significantly lower activity demonstrated by PEDF when given in a
more advanced phase of liver disease raises some doubts concerning its potential to
add something for the treatment of clinically significant PHT. However, since a modest
effect on portal pressure is observed even in advanced cirrhosis, the combination
of PEDF with vasoactive drugs deserves further experimental investigation, with the
hope that working simultaneously on more therapeutic targets will maximise the impact
on portal pressure.
In conclusion, the data presented in this study highlights again the importance of
targeting VEGF-driven angiogenesis and reveals new important insights into the molecular
working mechanism of PEDF as a possible antiangiogenic and antifibrotic agent in the
treatment of early phase PHT. Hence, the next step should be trying to translate these
findings into clinical practice, where PEDF needs to confirm its capability to halt
the rise of portal pressure, and to prove it can add something, eventually in association
with or without non-selective β-blockers (NSβB)8 and/or anti-inflammatory agents,9
before clinical significant PHT has developed.