Myosin mediates contractile force generation by hepatic stellate cells in response to endothelin-1

Both Ca2+-dependent and -independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine

“…Accumulating evidence indicates that the contractile force generated by activated HSCs not only drives scar contraction in cirrhosis but also modulates the hepatic microcirculation (12,19,(22)(23)(24)26). Both aspects affect the increased IHVR to portal flow, and therefore make HSCs interesting targets for the treatment of portal hypertension.…”

“…We therefore tested Ca 2ϩ -independent pathways. Since these pathways are thought to converge in the inactivation of MLCP, resulting in delayed degradation of phosphorylated rMLC and thefore decreased contraction, we first focused on this enzyme (8,11,19,26,27). We demonstrated that the phosphatase inhibitor calyculin, in the absence of any agonist, could promote HSC contraction, proving its involvement in the regulation of force generation additive to the Ca 2ϩ -dependent pathway.…”

“…Phosphorylation of rMLC allows myosin ATPase to be activated by actin, leading to actomyosin crossbridging and cell contraction (21,28). In nonmuscle cells, including activated HSCs, increased phosphorylation of rMLC has also been correlated with increased contractility (11,26). However, in contrast to smooth muscle cells, several studies (10,19,27) favor non-Ca 2ϩ -dependent contraction pathways to be the key event in force generation by myofibroblasts, of which the RhoA signaling and PKC-dependent pathway are the most relevant.…”

Mechanisms of Hepatic Fibrogenesis

“…146 Contractility-Contraction of stellate cells contributes to increased portal resistance during liver fibrosis that presumably is reversible before the thickened septae, intrahepatic shunts, and lobular distortion of cirrhosis develop, leading to fixed increases in portal pressure. Even in earlier stages of fibrosis, activated stellate cells already show features of smooth muscle-like cells, characterized by expression of a number of contractile filaments including α smooth muscle actin 147 and myosin, 148 which generate calcium-dependent and calcium-independent contractile forces that contribute to cellular contractility. [149][150][151] Culture models increasingly recapitulate many of these smooth muscle features, in part by restoring a more physiologic substratum, as well as by including other resident cell types in a co-culture system, especially Kupffer cells.…”

Biomedical Vignette

“…However, the mechanisms that couple endothelin-1 to the generation of contractile force by stellate cells are not clearly defined. Saab et al [35] showed that endothelin-1 stimulates a rapid and dosedependent increase in contractile force in both primary cultures and immortalized stellate cells. They further found that the generated contractile force is mediated by myosin.…”