Transformation of sinusoids into capillaries in a rat model of selenium-induced nodular regenerative hyperplasia: An immunolight and immunoelectron microscopic study

Abstract

The oral administration of selenium (Se) to young rats induces, over a 2-month period, the formation of nodular regenerative hyperplasia with sinusoidal damage around nodules. Perinodular areas located in zone 1 comprise atrophic hepatocytes and capillarized sinusoids without fibrosis. We used this unique model of capillarization without fibrosis to investigate the temporal relationship between the process of capillarization and changes occurring in the deposition of components of the extracellular matrix. After 2 weeks of intoxication, type III collagen and fibronectin were stable, but laminin and type IV collagen had increased in zone 1, resulting in the formation of septae between portal tracts. Even at 8 weeks, these two components still formed the principal deposits in perinodular zones. Electron microscopy showed already at 1 week in zone 1 that part of the endothelial wall had detached from hepatocytes. Sinusoidal endothelial cells progressively acquired certain of the characteristics of a vascular endothelium, some proliferated, and perisinusoidal cells transformed into myofibroblasts, surrounded by deposits of laminin and type IV collagen. These results indicate that both laminin and type IV collagen are involved in capillarization without fibrosis and in angiogenesis; fibronectin would not seem to play a role.

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

“…The main distinction is that there is no increase in vessel number due to the anatomic constraints of the liver sieve plates. Capillarization of LSEC results in ultrastructural phenotypic conversion to endothelial cells with tight intercellular junctions and loss of fenestrations (Couvelard et al, 1993;Dubuisson et al, 1995;Xu et al, 2003). In multiple human and animal studies, capillarization has been demonstrated to precede alcohol-induced liver disease, portal hypertension, cirrhosis, and chronic hepatitis (DeLeve et al, 2004;Dubuisson et al, 1995;Tsuneyama et al, 2003;Xu et al, 2003).…”

“…Capillarization of LSEC results in ultrastructural phenotypic conversion to endothelial cells with tight intercellular junctions and loss of fenestrations (Couvelard et al, 1993;Dubuisson et al, 1995;Xu et al, 2003). In multiple human and animal studies, capillarization has been demonstrated to precede alcohol-induced liver disease, portal hypertension, cirrhosis, and chronic hepatitis (DeLeve et al, 2004;Dubuisson et al, 1995;Tsuneyama et al, 2003;Xu et al, 2003). Increased SEC membrane PECAM-1 protein expression and deposition of a laminin-1-containing basement membrane are hallmarks of capillarization in injured livers (Couvelard et al, 1993;DeLeve et al, 2004).…”

“…Instead, SEC angiogenesis is a dedifferentiation and maturation process called capillarization with diagnostic hallmarks of SEC defenestration and increased surface expression of PECAM-1 and laminin-1 protein (Braet et al, 2002;DeLeve et al, 2004;Couvelard et al, 1993;Guyot et al, 2006;Tsuneyama et al, 2003). The normally discontinuous SEC become a continuous endothelium with limited transendothelial cell transport due to loss of fenestrae and formation of tight intercellular endothelial junctions (Dubuisson et al, 1995;Braet et al, 2002;Xu et al, 2003;Couvelard et al, 1993). Capillarization precedes vascular remodeling of other liver vessels, such as the hepatic arterioles and the peribiliary vascular plexus causing the shunting of blood flow, vascular channel formation, and eventually liver fibrosis (Couvelard et al, 1993;DeLeve et al, 2004;Li et al, 2005).…”

Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF‐β as major players and therapeutic targets

“…Subendothelial matrix deposition (in the space of Disse) leads to incomplete basement membranes ("capillarization") [10,11], which hinder bidirectional exchange processes between hepatocytes and sinusoidal blood stream, and, thus, impairs the clearance function and the biosynthetic delivery function of the parenchymal tissue. Furthermore, narrowing of the sinusoidal lumen by perisinusoidal fibrosis is considered to be a contributing factor to intraparenchymal hemodynamic resistance (portal hypertension).…”

Hepatic Lesions Caused by Large Granular Lymphocyte Leukemia in Fischer 344 Rats

“…Similarly, in an animal model of hepatocarcinogenesis, sequential observation of the sinusoids within the tumor nodule demonstrated that the endothelial cells began to express FVIII-RAg and the number of Kupffer cells decreased as the arterial blood supply increased (Yamamoto et al 1996;Shoji et al 1994). FVIII-RAg expression in the sinusoids indicates sinusoidal capillarization (Schaffner and Popper 1963), which has also been observed in selenium-induced hepatic lesions (Dubuisson et al 1995). Therefore, FVIII-RAg expression and the lack of Kupffer cells in the hepatic sinusoids in the present study may also suggest that the main route of blood supply to the liver in cases with advanced LGL leukemia was the hepatic artery.…”