Hepatic blood flow regulation by stellate cells in normal and injured liver

Hepatic stellate cells have received considerable attention as key componen ts of the fibrogenic response to injury Beyond this feature, they also have been implicated as regulators of sinusoidal vascular tone, and in disease states, in the pathogenesis of intrahepatic portal hypertension. The basis for this latter concept is derived from the following: (a) stellate cells a re situated in a perisinusoidal orientation within the sinusoid, optimized for sinusoidal constriction; (b) a series of studies performed-over the pas t decade have demonstrated that perisinusoidal stellate cells exhibit a rem arkable capacity for cellular contraction, a characteristic that is most pr ominent after liver injury and stellate cell activation; and (c) in vivo mi croscopy studies have revealed that stellate cells can mediate sinusoidal c onstriction. Available evidence indicates that liver injury leads to a vasc ular disorder in which endothelin-1 is overproduced by stellate cells and e ndothelial cell-derived nitric oxide production is reduced. These abnormali ties, in the context of exaggerated stellate cell contractility after liver injury, set up a paradigm in which stellate cells contribute to the increa sed intrahepatic resistance typical of portal hypertension. Furthermore, be cause stellate cell contractility and the mediators that control this funct ion are dynamic processes, strategies that target exaggerated contractility provide an opportunity for novel therapeutics in intrahepatic portal hyper tension.