- Top of page
- Intrahepatic circulation
- Splanchnic and systemic circulations
- Future direction
Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide, and favours vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation and develops portal hypertension. Portal hypertension, in turn, causes endothelial dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike dysfunction in LSECs, endothelial dysfunction in the splanchnic and systemic circulation causes overproduction of vasodilator molecules, leading to arterial vasodilation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathological consequences, such as oesophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension has been elucidated, the underlying cellular and molecular mechanisms causing endothelial dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on endothelial dysfunctions found during the development of cirrhosis and portal hypertension with a focus on the intra- and extrahepatic circulations. The article ends by discussing the future directions of the study for endothelial dysfunction.
Portal hypertension is a detrimental complication resulting from cirrhosis (1, 2). Intra- and extrahepatic endothelial dysfunction is a key factor that causes and worsens portal hypertension (3) (Fig. 1). In the intrahepatic microcirculation, hypoactive endothelial cells contribute to an increased intrahepatic resistance mainly by decreasing nitric oxide (NO) production, which in turn initiates portal hypertension. Portal hypertension, once it develops, affects extrahepatic vascular beds in the splanchnic and systemic circulation, leading to arterial vasodilation and collateral vessel formation, resulting in greater blood flow into the portal vein. This increase in portal blood flow further exacerbates portal hypertension (1, 2). In contrast to hypoactive endothelial cells in the intrahepatic microcirculation, endothelial cells in the splanchnic and systemic circulation are hyperactive and increase NO production. Thus, endothelial cells with opposing phenotypes are found in the intra- vs. extrahepatic circulation. Both contribute to the development and exacerbation of portal hypertension (3).
Figure 1. Overview of the development and consequences of portal hypertension in cirrhosis. Endothelial dysfunction plays important roles in the pathophysiology of portal hypertension. LSEC; liver sinusoidal endothelial cell.
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With knowledge of vascular biology, our understanding of the pathogenesis of portal hypertension has significantly advanced, revealing how vascular abnormalities both in and outside the liver contribute to portal hypertension, i.e. how these endothelial dysfunctions relate to those vascular abnormalities. However, how these endothelial dysfunctions occur in cirrhosis and portal hypertension still remains to be elucidated, particularly at the cellular and molecular levels.
This review article thus summarizes current cellular and molecular studies on endothelial dysfunctions in cirrhosis and portal hypertension, first in the area of the intrahepatic/sinusoidal microcirculation and second in the extrahepatic, i.e. splanchnic and systemic, circulation. This article concludes with a discussion of the future directions that the study of endothelial dysfunctions and the vascular abnormalities associated with them will take in relation to cirrhosis and portal hypertension. This review article focuses on endothelial cells. However, other cell types, such as hepatic stellate cells (HSCs), smooth muscle cells and Kupffer cells, are equally important to endothelial dysfunctions and the subsequent vascular changes found in cirrhosis and portal hypertension.