Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: Localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction

Abstract

Portal hypertension is a clinical syndrome caused by a pathological increase in portal pressure usually accompanied by complications such as ascites, esophageal varices, and hepatic encephalopathy. In cirrhosis, decreased sinusoidal caliber and impaired sinusoidal wall elasticity are considered to be responsible for the increased portal pressure. [1][2][3] In addition to structural changes, humoral factors with vasoactivity may modify the resistance of portal vasculature and contribute to the pathogenesis. Endothelin-1 (ET-1), a peptide produced by vascular endothelial cells, induces strong contraction of perivascular smooth muscles. 4 The liver is considered to be particularly sensitive to the constriction action of ET-1 because systemic infusion of low-dose ET-1, which exerts relatively little effect on systemic pressure, can cause an increase in portal pressure. 5 Elevation of portal pressure occurs more dramatically by the intraportal infusion of ET-1. 5,6 The sinusoids and presinusoidal portal venules were thought to be involved. 5 It is demonstrated that endotoxin 7 and thrombin 8 enhance synthesis of ET by endothelial cells. In clinical practice, plasma ET levels are significantly elevated in the patients with cirrhosis. 9 These studies raise the possibility that ET-1 may be involved in the pathogenesis of portal hypertension in various liver diseases.In regard to the regulatory mechanism along the anatomical pathway for the intrahepatic portal blood flow, the main site of resistance in the normal liver is an unsolved, controversial issue. Intrahepatic portal branches, hepatic sinusoids, and central veins, however, have been similarly suggested. 10 Intrahepatic portal system consists of conducting veins and distributing veins. 11 Conducting veins consist of interlobar veins, segmental veins, and interlobular veins with a diameter of larger than 300 to 400 mm. Distributing veins, which are characterized by the presence of inlet venules, include preterminal portal venules (PPV) and terminal portal venules, the latter of which are also termed septal branches. 12 By definition, PPV are the axial vessels of the complex acini and are localized at the corner of the liver lobule, and the terminal portal venules are the axial vessels of the simple acini. 11 Both vessels constitute the basic organization of the primary lobules as defined by Matsumoto et al. 12 This study was designed to reveal the major site of vascular constriction in the porto-sinusoidal system in response to ET-1 and resultant alterations of intrahepatic circulation. We used an in situ liver perfusion model with ET-1 at a constant flow rate to morphologically detect the intrahepatic heterogeneity of vasoconstrictive effects along the portal tree and the subsequent inhomogeneity of flow distribution under increased portal pressure.Abbreviations: ET-1, endothelin-1; PPV, preterminal portal venules; DS/PPV, distal segment of preterminal portal venules; PS/PPV, proximal segement of preterminal portal venules; KHB, Krebs-Henseleit buffer.From the

Enhanced expression of endothelin B receptor at protein and gene levels in human cirrhotic liver

“…On the other hand, Kaneda et al demonstrated that the parenchyma of ET-1 perfused liver in rat was distinguished histologically into two areas; one consisted of loosely woven plate of vacuolated hepatocytes with widened sinusoids, and the other with closely packed hepatic cell plates intervened by narrowed, collapsed sinusoids concomitant with constriction of preterminal portal venules. 36 Increased ETBR may mediate cell contraction and increase hepatic sinusoidal microvascular tone, and contribute to portal hypertension.…”

Vascular mediators in the injured liver

“…Intrahepatic resistance, and thus blood flow, may be modulated at several of these sites. [3][4][5] Vascular smooth muscle cells in terminal portal venules and hepatic venules have been presumed to be the major sites of pre-and postsinusoidal vascular resistance, whereas the hepatic sinusoids have been compared with capillary beds in other tissues, in which smooth-muscle-like pericytes regulate blood flow. 6 In the sinusoid, endothelial cells and hepatic stellate cells have been identified as the cellular elements most likely to be important in regulation of resistance, 4,7,8 with most data pointing to stellate cells.…”

Sublobular veins as the main site of lymphocyte adhesion/transmigration and adhesion molecule expression in the porto-sinusoidal-hepatic venous system during concanavalin A-induced hepatitis in mice

“…11 Corresponding to such low blood pressures, intrahepatic portal veins, in spite of their responsibility for conducting and distributing parenchymal blood flow, are invested with only 1 or 2 layers of smooth muscle cells or are even lacking them in places. 12 Furthermore, hepatic sinusoids consist of fenestrated endothelium and incomplete basement membrane different from capillaries. From these facts, it is expected that the location and mechanism of leukocyte margination/emigration in the hepatic vasculature might be different from those in the organs with a high-pressure circulatory system.…”