The Hepatic Microvascular System in Health and Its Response to Toxicants

Abstract

This review briefly summarizes what is known about the dynamic morphology of the hepatic microvascular system that includes all vessels in the liver with a diameter less than 300 mm and various morphological sites within these vessels that regulate the distribution of blood flow. The latter include the various segments of the afferent portal venules and hepatic arterioles, the sinusoids, and central and hepatic venules. Sinusoids are unique exchange vessels lined by fenestrated endothelial cells which have important endocytotic functions and phagocytic Kupffer cells which are important for host defense. These are encircled by extraluminal stellate cells that are specialized pericytes containing fat droplets that store vitamin A. The principle sites for regulating blood flow are in the sinusoidal network with stellate and endothelial cells playing a major role in regulating the diameters of sinusoids and the distribution of blood flow in individual sinusoids, lobules, or segments of lobules. The sinusoidal endothelial cells are a sensitive and early target for several toxicants. For example, as early as 30 minutes after the administration of acetaminophen, the endothelial cells become swollen and begin to lose the ability to endocytose ligands. Within 2 hr, gaps through the cytoplasm appear formed by the destruction and/or coalescence of fenestrae which permit red blood cells to penetrate into the space of Disse. Subsequently, the sinusoid may collapse or disintegrate reducing blood flow. Anat Rec, 291:661-671,

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

“…In addition, VEGF alters vascular permeability (Senger et al, 1983), which could affect hepatic microcirculation. Previous data have shown that hepatic microvascular injury, including sinusoidal cell injury, occurs early in APAP toxicity (Walker et al, 1985;McCuskey, 2006McCuskey, , 2008. Because HA is cleared by normal endothelial cells, increased levels of plasma HA represent a functional marker of sinusoidal cell injury.…”

“…9B). Changes in the cellular integrity of the hepatic sinusoid have been described in APAP toxicity (Walker et al, 1985; McCuskey, 2006McCuskey, , 2008 and include the development of large pores in the sinusoidal endothelial cells and the filling of the space of Disse with red blood cells (Walker et al, 1985). HA is cleared by normal sinusoidal endothelial cells, and with the onset of sinusoidal endothelial cell injury HA levels in plasma rise.…”

Immune Functioning in Non lymphoid Organs: The Liver

“…This specialized endothelium is fenestrated and generally lacks a basal lamina, thus solutes and small particles have direct access to the peri-sinuoidal space that contains processes of stellate cells and microvilli of hepatocytes (McCuskey 2008). The fenestrations are true discontinuities in the endothelium, having neither a diaphragm nor an underlying basal lamina.…”

Long-Term Coculture Strategies for Primary Hepatocytes and Liver Sinusoidal Endothelial Cells

“…[22][23][24][25] While hepatocytes are primarily responsible for various secretion and metabolic functions of the liver; LSECs line the sinusoids, isolating hepatocytes from the sinusoid flow and are first to be exposed to various toxic and benign factors circulating through the hepatic sinusoids. [26][27][28] There is growing evidence that LSECs also participate in various metabolic activities, and are the primary target for some hepatic toxicants. 15,[29][30][31][32][33][34] Although LSECs have a significant role in drug exposure and toxicity, their use in drug screening, alongside hepatocytes, is limited as they lose their phenotype rapidly after isolation and are not viable in monoculture beyond a few days.…”