New cellular and molecular targets for the treatment of portal hypertension

Abstract

Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.

Effects of aging on liver microcirculatory function and sinusoidal phenotype

“…Further analysis revealed a global deregulation in the hepatic endothelial phenotype in aging as demonstrated by significant decrease in key vasodilatory pathways, including nitric oxide and heme oxygenase, increment in intracellular inflammation and oxidative stress, and reduction in the expression of functional and angiocrine markers such as stabilin‐2, CD32b (Xie et al, 2013), and VEGFR2 (Carpenter et al, 2005). Reduction in intrahepatic nitric oxide availability is of relevance considering its importance modulating the vascular tone (Gracia‐Sancho, Maeso‐Diaz, Fernandez‐Iglesias, Navarro‐Zornoza, & Bosch, 2015; Hori, Wiest, & Groszmann, 1998), exerting anti‐inflammatory effects (Iwakiri & Kim, 2015), and maintaining neighboring cells phenotype (Marrone et al, 2016; Xie et al, 2013). Reduced nitric oxide bioavailability might, at least in part, derive from diminished eNOS activity, which may be due to reduced VEGF‐p‐eNOS pathway (Kroll & Waltenberger, 1998), and from increased scavenging due to elevated oxidative stress (Gracia‐Sancho et al, 2008).…”

“…Many efforts are currently being directed toward the development of novel therapeutic approaches for portal hypertension (Gracia‐Sancho et al, 2015). Most preclinical studies on the effects of different substances and drugs on the liver circulation have been conducted in young animals.…”

The profile of platelet α‐granule released molecules affects postoperative liver regeneration

“…Indeed, experimental studies suggest a central relevance of portal blood flow to platelet activation. Whereas shear stress itself affects platelet activation, endothelial cell damage caused by increased intrahepatic vascular pressure can additionally modify platelet activation …”

Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis‐PROX1‐HIF‐1α in liver fibrosis

“…Vascular endothelium represents the interface between blood and other tissues of the body. Not only it is a physical barrier but also it is implicated in different physiological roles, such as haemostasis/ thrombosis, metabolites transportation, inflammation, angiogenesis and vascular tone . Liver endothelium is made up of LSECs and adjacent HSCs.…”