Endothelial Dysfunction and Liver Cirrhosis: Unraveling of a Complex Relationship

Abstract

Endothelial dysfunction (ED) is the in the background of multiple metabolic diseases and a key process in liver disease progression and cirrhosis decompensation. ED affects liver sinusoidal endothelial cells (LSECs) in response to different damaging agents, causing their progressive dedifferentiation, unavoidably associated with an increase in intrahepatic resistance that leads to portal hypertension and hyperdynamic circulation with increased cardiac output and low peripheral artery resistance. These changes are driven by a continuous interplay between different hepatic cell types, invariably leading to increased reactive oxygen species (ROS) formation, increased release of pro-inflammatory cytokines and chemokines, and reduced nitric oxide (NO) bioavailability, with a subsequent loss of proper vascular tone regulation and fibrosis development. ED evaluation is often accomplished by serum markers and the flow-mediated dilation (FMD) measurement of the brachial artery to assess its NO-dependent response to shear stress, which usually decreases in ED. In the context of liver cirrhosis, the ED assessment could help understand the complex hemodynamic changes occurring in the early and late stages of the disease. However, the instauration of a hyperdynamic state and the different NO bioavailability in intrahepatic and systemic circulation-often defined as the NO paradox-must be considered confounding factors during FMD analysis. The primary purpose of this review is to describe the main features of ED and highlight the key findings of the dynamic and intriguing relationship between ED and liver disease. We will also focus on the significance of FMD evaluation in this setting, pointing out its key role as a therapeutic target in the never-ending battle against liver cirrhosis progression.

Keywords: Krüppel-like factor; albumin; cirrhosis; endothelial dysfunction; endothelium; flow-mediated dilation; nitric oxide; shear stress; statins.

Figure 1

Main features of healthy and dysfunctional vascular endothelium. In homeostatic conditions, a healthy endothelium is a thin monolayer of endothelial cells at the interface between the circulatory system and tissues. Under normal circumstances, endothelium regulates vascular tone, hemostasis, inflammation, permeability, and oxidative stress, providing a natural barrier to bloodborne pathogens, thus maintaining an antioxidant, anti-inflammatory, anti-thrombotic, and anti-proliferative milieu. However, cardiovascular risk factors prompt the disruption of the endothelial barrier function through molecular and mechanic pathways such as inflammation, with the activation of NLRP3 and pro-inflammatory cytokine release, ROS overproduction and the consequent reduction in NO bioavailability, and shear stress impairment. This leads to deleterious vasoconstriction and a switch toward a pro-oxidant and proliferative condition, associated with increased vascular permeability, thrombosis, and inflammation. NLRP3: Nod-Like Receptor Protein 3; NO: nitric oxide; ROS: reactive oxygen species; IBD: inflammatory bowel diseases.

Figure 2

Intrahepatic endothelial dysfunction. In normal conditions, NO production by LSECs, physiologically driven by shear stress through the upregulation of KLF2 transcription, controls vascular tone, and mantains HSCs quiescence. In case of liver injury, aside from the etiology (i.e., alcohol, HFD, viral hepatitis, LPS), this delicate balance is disrupted; LSECs lose their fenestrae and acquire basal membrane in a process defined as “capillarization”. As a result, shear stress increases, but the intrahepatic concentration of NO decreases because of changes in LSEC phenotypes and aberrant ROS production by injured hepatocites. Within the sinusoidal lumen, KCs are activated by liver damaging agents, with the subsequent release of pro-inflammatory cytokines and chemokines and the increased expression of vascular adhesion molecules such as VCAM on LSECs, which further stimulate monocytes differentiation into inflammatory, angiogenic, and fibrogenic macrophages. Activated KCs promote collagen production by HSCs and MFs through the release of several mediators, such as TGFβ1 and PDGF, also capable of enhancing MF survival through the stimulation of NF-kB transcription, also triggered by the increased release of ROS. In parallel, the increase in shear stress interacts with mechanosensitive calcium channels promoting CXCL1 expression, a neutrophil chemoattractant; neutrophils promote NETs formation which favor microvascular thrombosis and liver injury progression, with subsequent IHVR increase and portal hypertension development. NO: nitric oxide; KLF: Krüppel-like factor; HSCs: hepatic stellate cells; ROS: reactive oxygen species; HFD: high fat diet; LPS: lipopolysaccharide; LSECs: liver sinusoidal endothelial cells; KC: Kupffer cell; VCAM: vascular cell adhesion molecule; TGF-β1: Transforming growth factor beta 1; PDGF: platelet-derived growth factor; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; CXCL1: chemokine (C-X-C motif) ligand 1; MF: myofibroblasts; IHVR: intrahepatic vascular resistance.

Figure 3

(A). Bile acid (BA) homeostasis is essential to preserve not only the liver homeostasis, but also the endothelial function. Among BA receptors, TGR5 and FXR are the most studied. TGR5 is expressed not only on hepatocytes cellular membrane, but also on LSECs endothelial cells and macrophages and exert their vasodilatory action by increasing NO expression and decreasing ET-1 levels; furthermore, it preserves the hepatic and endothelial function by modulating cytokine secretion. (B). When BA homeostasis is disrupted and their composition changes, altering the balance between the hydrophobic and the hydrophilic component, cellular and mitochondrial membranes of hepatocytes and intestinal cells can be damaged, causing apoptosis. In the gut, BAs alter tight junctions and increase intestinal permeability, bacterial translocation, and lipopolysaccharide concentration. Together with the direct damage of the liver, the activation of these pathways is responsible for the increased intrahepatic vascular resistance that accompanies liver disease progression and the endothelial dysfunction. BAs: bile acids; NO: nitric oxide; LPS: lipopolysaccharide; ECs: endothelial cells; LSECs: liver sinusoidal endothelial cells; TGR5: Takeda G-protein associated receptor TGR5; FXR: Farnesoid X receptor; ET-1: Endothelin-1; TJ: tight junction.

Figure 4

Experimental therapies used against liver cirrhosis and clinically significant portal hypertension have proved benefits in relieving endothelial dysfunction and its vicious circle, made up of inflammation, pro- and antioxidant imbalance, and shear stress impairment. Albumin has shown to exert non-oncotic properties with antioxidant, anti-inflammatory, and immunomodulatory features. Statins have demonstrated a role as anti-fibrotic, anti-proliferative, and antioxidant agents, thus ameliorating LSEC function and decreasing intra-hepatic resistance. Anticoagulants and PPAR agonists, such as pioglitazone and fibrates, have shown to improve portal hypertension through anti-angiogenetic, anti-inflammatory and anti-proliferative pathways. FXR agonists remodulate bile acid homeostasis with the subsequent preservation of hepatocytes and amelioration of the endothelial and gut–vascular barrier function. LSECs: liver sinusoidal endothelial cells. PPAR: peroxisome proliferator-activated receptor.