Regulatory mechanisms of hepatic microcirculation.

Hepatic microvasculature receives blood from two types of afferent vessels: the terminal portal venule (TPVn) and the terminal hepatic arteriole (THAo). The TPVns directly connect with the capillary bed in the liver parenchyma, which is referred to as sinusoids. Hepatic arterial blood pours into the hepatic sinusoids not only indirectly via the anastomosis between the THAo and the portal venule (PVn), but also directly through the THAo or the capillaries derived from the arterial capillary network around the bile duct. From a regulatory point of view, the hepatic arterial system is considered to be supplementary, but hepatic arterial flow is essential for supplying oxygen to sinusoidal blood flow as well as to the bile ducts, portal venules and nerves in the portal tract. The main regulators of hepatic sinusoidal blood flow are present in the portal venous system. By intravital and scanning electron microscopy, it is evident that a potent vasoconstrictor endothelin (ET)-1 causes a contraction of the SEF via the ET_B receptors, as well as a significant contraction of the PVn and TPVn, resulting in an increase in sinusoidal and pre-sinusoidal microvascular resistance. This phenomenon implies that the TPVn, particularly the transitional part to the sinusoid, would provide an essential regulatory site for hepatic sinusoidal blood flow as an inlet sphincter-like function. The endothelial cell linings along the hepatic sinusoids are characterized by the presence of a large number of sieve plate-like pores, 100 nm in diameter, i.e. the sinusoidal endothelial fenestrae (SEF). The SEF are dynamic structures, forming the racemose invaginations of the endothelial plasma membrane across the endothelium, and regulating not only the permeability of hepatic sinusoids, but also the sinusoidal blood flow by the Ca++ -actomyosin-mediated contraction and dilatation of the SEF. Our recent immunoelectron microscopic and Western blot studies have revealed that caveolin-1, i.e. the principal structural protein of caveolae, and endothelial nitric oxide synthase (eNOS) co-exist in the plasma membrane of the SEF, implying that the SEF may correspond to a permanent (stationary) type of fused and interconnected caveolae, thus contributing to the local control of hepatic sinusoidal blood flow by the regulation of NO synthesis.