Quantitation of rat hepatic stellate cell contraction: stellate cells’ contribution to sinusoidal resistance

Thimgan, Matthew S.; Yee, Hal F.

doi:10.1152/ajpgi.1999.277.1.g137

Cited by 57 publications

(67 citation statements)

References 24 publications

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“…Transduction of these cells is particularly intriguing, because these cells contain the downstream signaling targets, including soluble guanylate cyclase, necessary to influence vascular tone in response to NO as well as other vasodilator molecules such as CO (14,15,19,26,28). We and others (3,22,23,31) have previously demonstrated that caveolin-1 protein abundance is increased in cholestatic and noncholestatic models of chronic liver injury and cirrhosis within liver endothelial cells and that this may contribute to deficient hepatic eNOS activity in these models.…”

Section: Discussionmentioning

confidence: 99%

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

Hendrickson

Chatterjee

Cao

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

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Section: Discussionmentioning

confidence: 99%

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

Hendrickson

Chatterjee

Cao

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In fact, factors capable of inducing contractile forces in HSCs, such as endothelin, also cause a marked reduction of cell area in activated HSCs, as described previously. 13,27 This reduction in cell area induced by vasoconstrictors is antagonized by preincubation of cells with vasodilator factors, such as nitric oxide, prostaglandins, or atrial natriuretic peptides. 28,29 Moreover, a close relationship between Ca 2ϩ mobilization and reduction in cell area in human HSCs has been shown.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels

et al. 2001

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Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells, which develop contractile properties and contribute to increased resistance to blood flow. We investigated whether this phenotypic activation includes changes in the expression of L-type voltage-operated Ca 2؉ channels (VOCC), which mediate Ca 2؉ influx and regulate cell contraction in vascular cell types. Rat HSCs were studied in the quiescent phenotype and after their activation in vitro (cultured on plastic for 14 days) and in vivo (isolated from rats with CCl 4 -induced cirrhosis). Patch-clamp studies showed Ca 2؉ currents through L-type VOCC in HSCs activated both in vitro and in vivo, whereas no currents were detected in quiescent HSCs. Moreover, binding studies with 3 H-isradipine, a specific L-type VOCC antagonist, showed a large number of binding sites in activated HSCs, while no specific binding was found in quiescent HSCs. In chronic liver diseases, hepatic stellate cells (HSCs) transdifferentiate from a quiescent phenotype into a myofibroblastlike phenotype, a process also named "activation." 1,2 The most relevant consequence of this phenotypic activation is the increased secretion of components of the extracellular matrix, a key feature in liver fibrogenesis. 3 In addition, recent data indicate that another important consequence of this process is the acquisition of contractile properties. 4 Due to their strategic anatomical location around hepatic sinusoids, tonic contraction of activated HSCs in response to agonists may increase sinusoidal resistance to blood flow and thus play an important role in the pathogenesis of portal hypertension in advanced chronic liver diseases. 5,6 In the last decade, much attention has been focused on the molecular mechanisms responsible for the increased collagen synthesis that display HSCs following phenotypic activation. 7 In clear contrast with these advances, the mechanisms by which the phenotypic activation of HSCs results in increased cell contractility remain largely unknown. Studies using in vitro and in vivo models of HSC activation have constantly shown that activated HSCs express high amounts of ␣-smooth muscle actin and myosin, cytosolic proteins essential for cell contractility, which are absent in quiescent HSCs. 8,9 Moreover, recent data indicate that in vitro activation of HSCs results in increased sensitivity to vasoconstrictor and depolarizing substances when assessed in terms of Ca 2ϩ mobilization. 10,11 However, the mechanisms underlying this increased Ca 2ϩ response are unknown. In human activated HSCs, an agonist-induced increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is largely mediated by the opening of L-type voltage-operated Ca 2ϩ channels (VOCC), 12,13 which are known to regulate Ca 2ϩ entry and thereby cell contraction in other vascular cell types. 14 We hypothesized that the process of activation of HSCs is associated with changes in the expression of L-type VOCC that mediate Ca 2ϩ mobilization and cell contraction. ...

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“…Regardless, studies evaluating the hepatic microcirculation by intravital microscopy techniques have suggested that HSC could be involved in the regulation of sinusoidal tone in normal liver (45,46). Additional matter of debate is provided by studies aimed at quantitating HSC contraction with techniques able to detect the development of contractile forces in response to vasoconstrictors (47). The results of these studies indicate that the magnitude and kinetics of contraction and relaxation are consistent with the hypothesis that HSC may affect sinusoidal resistance.…”

Section: Hscmentioning

confidence: 91%

Anatomy and Vascular Biology of the Cells in the Portal Circulation

Pinzani

Vizzutti

Clinical Gastroenterology

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Quantitation of rat hepatic stellate cell contraction: stellate cells’ contribution to sinusoidal resistance

Cited by 57 publications

References 24 publications

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels

Anatomy and Vascular Biology of the Cells in the Portal Circulation

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