Fig. 1.

Angiodiversity of the hepatic endothelium. Nutrient-rich blood from the gastrointestinal tract enters the sinusoid via the portal vein and mixes with oxygen-rich blood from the hepatic artery. The blood then moves through the fenestrated sinusoidal vasculature and exits the liver via the central vein creating an oxygen and blood flow gradient along the axis of the liver lobule. These physical gradients establish a “zonation” of hepatocytes and LSEC. Hepatocytes adjacent to the portal vein show high gluconeogenesis, urea synthesis, and beta oxidation activity. In turn, pericentral hepatocytes are characterized with increased glycolysis, bile synthesis, xenobiotics metabolism, and triglyceride synthesis. Fenestrations of LSEC are larger in the periportal area, whereas they are more abundant in pericentral regions. Pericentral LSEC modulate the spatial division of hepatocytes by secreting angiocrine Wnt ligands and Wnt-signaling enhancer Rspo3. The hepatic microenvironment is mainly determined by the interplay of the four major cell populations, namely hepatocytes, LSEC, HSC, and KC. While KC are located in the sinusoids, HSC reside in the space of Disse, which is a perisinusoidal space between LSEC and hepatocytes