Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

Abstract

Summary Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system’s cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm’s law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well as those in the mesenteric vascular circulation. Translational implications of recent research and the future directions that it points to are also highlighted.

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…There is increasing evidence that neovascularization is a key element in the progression of NAFLD [56,57]. Formation of new blood vessels in chronic liver disease is linked to the advancement of fibrosis, indicating a close interplay between LSECs and HSCs.…”

“…Formation of new blood vessels in chronic liver disease is linked to the advancement of fibrosis, indicating a close interplay between LSECs and HSCs. Vascular endothelial growth factor (VEGF) is the master regulator of this process, mediating both pro-fibrogenic and pro-angiogenic signals and supported by HIF activation in hypoxic areas [57]. Importantly, serum VEGF levels of patients with steatosis and steatohepatitis are higher compared to healthy controls [56].…”

“…Many vasoactive substances such as NO, glucagon, bile salts, platelet-activating factor, calcitonin gene-related peptide, atrial natriuretic peptide, adrenomedullin, and endocannabinoids have been implicated in arteriolar vasodilation in the visceral vascular bed that drains into portal circulation and causes increased portal inflow [7,57]. These mediators may reach higher splanchnic concentrations due to impaired liver metabolism or increased portosystemic shunting [62].…”

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…The hepatic sinusoids with the involved hepatic sinusoidal endothelial cells (SEC), smooth muscle cells, and pericytelike hepatic stellate cells (HSC) form an intrahepatic microcirculatory unit, where these cells are intimately associated with one another and communicate through paracrine and autocrine effects [1]. Changes in this microenvironment are crucial in the early steps of fibrogenesis and include sinusoidal remodeling, vasoconstriction, endothelial dysfunction, and angiogenesis [2].…”

Assessment of splanchnic hemodynamics in patients with cirrhosis after portocaval shunting in comparison with no-operated patients with the compensated and decompensated course of disease

“…Гемодинамической основой цирроза печени (ЦП) является дисбаланс между артериальной, пор-тальной, кавальной и микроциркуляторной сосуди-стыми системами печени, определяющий развитие фиброза, патологическую регенерацию и синдром портальной гипертензии [1][2][3][4]. Изменения микроцир-куляторного русла печени характеризуются снижени-ем эффективного портального (синусоидального) кро-вотока вследствие соединительнотканного замещения паренхимы (синусоидов) и усилением артериального вследствие артериального неоангиогенеза (артери-альной капилляризации).…”