CONCISE REVIEW IN MECHANISMS OF DISEASE Vascular Mediators in the Injured Liver

The vasculature plays a critical role in multiple physiologic and pathophysiologic processes. A number of recent advances have led to renewed focus on the vasculature in the liver. In patients with chronic liver disease, 3 general vascular beds are of importance. These include the peripheral vasculature, the mesenteric vascular bed, and the intrahepatic microcirculatory unit; abnormalities exist in each. For example, vasodilation and reduced resistance in the peripheral and mesenteric vasculature appear to be a result of increased activity of endothelial cell nitric oxide (NO) synthase (NOS) and enhanced NO production1 (also see Wiest and Groszmann2 for review). In contrast, the intrahepatic microcirculation is characterized by increased resistance, the basis of which appears to be multifactorial. This review focuses primarily on the intrahepatic vasculature and the mediators that affect it. The intrahepatic microvascular unit is made up of several discrete units, including portal venules, hepatic arterioles, sinusoids, central venules, and lymphatics. Intrahepatic resistance, and thus blood flow, may be modulated at several of these sites.3-5 Vascular smooth muscle cells in terminal portal venules and hepatic venules have been presumed to be the major sites of preand 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. Importantly, these two cells are intimately associated with each other and have paracrine effects on one another. For example, NO released by sinusoidal endothelial cells appears to have relaxing effects on stellate cells. Stellate cells possess extensive long, branching, intersinusoidal, and perisinusoidal cytoplasmic processes9 and have been shown to contract in situ in the normal sinusoid.10-12 Stellate cell contractility has been studied extensively in isolated cell systems13-15 —a number of vasoactive substances have been reported to have effects on stellate cells. Although controversy exists regarding the magnitude of stellate cell contraction in the normal liver, available data emphasize that stellate cells in the injured liver exhibit increased contractility and moreover, the degree of contraction appears to be proportional to the degree of liver injury.16,17 The mechanism for enhanced stellate cell contractility is coupled to enhanced expression of smooth muscle proteins and modified signaling pathways after their activation (see below for discussion of the activation process).18,19 In aggregate, these data suggest a prominent role for stellate cells in the regulation of intrahepatic resistance. Cellular components of the intrahepatic vasculature (i.e., endothelial cells, smooth muscle cells, and stellate cells) play an important role in vascular responses, as do the specific vasoactive compounds that exert effects on them. A number of vasoactive mediators have received attention, including vasoconstrictors such as endothelin (ET) and angiotensin II, and relaxing agents such as NO and carbon dioxide. Not only are hepatic stellate cells thought to be an important functional component of the intrahepatic microcirculatory unit, but a large body of literature has emphasized their role in hepatic fibrogenesis. In this regard, a number of vasoactive agents appear to have potent fibrogenic effects on stellate cells. Thus, this review will additionally review the putative role of vascular mediators in the fibrogenic response to injury.