Alteration of intrahepatic microcirculation in cirrhotic livers

Abstract

From a hemodynamic point of view, hepatic vascular resistance and portal inflow determine the level of portal pressure. Factors that determine hepatic vascular resistance include both structural and dynamic components. Among the structural components are histological characteristics such as steatosis, fibrosis, regeneration nodules, and neo-angiogenesis. Dynamic structures include cells with contractile properties such as hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells. The contributions of the interactions between four cells in cirrhotic livers resulted in hepatic endothelial dysfunction, hepatic microcirculatory dysfunction, hepatic venous dysregulation, hepatic fibrogenesis, and subsequently increased intrahepatic resistance and portal hypertension in cirrhosis. The pathogenic mechanisms that trigger the associated abnormalities in hepatic microcirculations include persistent endotoxemia, increased hepatic oxidative stress, activated endocannabinoids substances, pathogenic sinusoidal remodeling, and hypoperfusion in cirrhotic livers. Cumulative data suggested that various therapeutic strategies targeting hepatic microcirculation provided effective improvement of the systemic abnormalities of cirrhosis. Accordingly, the mechanistic and therapeutic approaches focusing on the disarrangement of hepatic microcirculation will be introduced in this article.

Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis

“…Indeed, AEA levels were elevated in circulating macrophages of cirrhotic rats and patients [192,193]. Together with the increased expression of CB 1 receptors in mesenteric arteries, the vasodilatory property of increased levels of AEA was even higher [194,195,196]. These findings suggest AEA as a mediator of splanchnic vasodilation in cirrhosis in a NO independent manner [128].…”

Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

“…In this haemodynamic disturbance, mesenteric splanchnic vasodilation and hepatic vascular resistance play an essential role (see Baldassarre et al ., ; Yang and Lin, ). The ECS is up‐regulated in human and experimental cirrhosis, as a higher plasma AEA level was found in patients (also increased PEA and oleamide levels; Caraceni et al ., ) and in rats with experimental cirrhosis (see Baldassarre et al ., ; Yang and Lin, ). AEA caused a stronger CB 1 and TRPV1 receptor‐dependent vasodilatation of mesenteric, but not femoral, arteries isolated from cirrhotic rats, in comparison with their controls (Domenicali et al ., ).…”

“…On the other hand, AEA caused vasoconstriction in the isolated perfused liver, which was more marked for rats with cirrhosis induced by bile duct ligation than for their controls. The increased intrahepatic resistance was correlated with the release of TXA 2 (Yang and Lin, ). Blockade of CB 1 receptors by acute or chronic rimonabant administration and/or CB 1 receptor deficiency increased the splanchnic vascular resistance in cirrhotic animals, leading to a concomitant decrease in the mesenteric arterial blood flow, reduced liver fibrosis and finally decreased PH and/or improved survival in different models of chronic liver damage.…”

“…Portal hypertension (PH) is one of the most severe complications of liver cirrhosis, which in turn is a leading cause of death and liver transplantation. In this haemodynamic disturbance, mesenteric splanchnic vasodilation and hepatic vascular resistance play an essential role (see Baldassarre et al ., ; Yang and Lin, ). The ECS is up‐regulated in human and experimental cirrhosis, as a higher plasma AEA level was found in patients (also increased PEA and oleamide levels; Caraceni et al ., ) and in rats with experimental cirrhosis (see Baldassarre et al ., ; Yang and Lin, ).…”

Review article: the role of the microcirculation in liver cirrhosis

“…Angiogenesis results in new vessel formation and shunting between pre‐ and post‐sinusoidal vessels . A rise in portal vein pressure is seen due to inadequate dilatation of poorly compliant abnormal intrahepatic neo‐angiogenic vessels . The new vessels themselves also further perpetuate the inflammatory response by expressing adhesion molecules and chemokines promoting the recruitment of inflammatory cells …”