Hepatic microcirculation and mechanisms of portal hypertension

Gracia‐Sancho, Jordi; Marrone, Giusi; Fernández‐Iglesias, Anabel

doi:10.1038/s41575-018-0097-3

Cited by 162 publications

(148 citation statements)

References 213 publications

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…Our current study, however, further demonstrates the ability of emricasan to promote fibrosis regression in a model of very advanced liver disease, as exemplified by cirrhotic rats with ascites. In addition to HSCs, LSECs represent an important component of the hepatic sinusoid with essential roles modulating hepatic vascular tone, inflammation, and hemostasis . Herein we describe global improvement in the LSEC phenotype and function, as demonstrated by increased NO bioavailability, which has important vasodilatory effects.…”

Section: Discussionmentioning

confidence: 92%

“…Underlying mechanisms explaining the improvement in portal hypertension were diverse and included benefits on both vascular and architectural components of the increased hepatic vascular resistance . Liver microvascular dysfunction leads to increased hepatic vascular tone, a key factor in PP elevation in cirrhosis, and was significantly improved in animals treated with emricasan.…”

Section: Discussionmentioning

confidence: 99%

“…Advanced chronic liver disease (ACLD) is characterized by the presence of regenerative nodules surrounded by fibrous septa, causing a marked architectural distortion, eventually leading to portal hypertension and liver failure . Progression of cirrhosis encompasses multiple coordinated cellular de‐regulations, including initial injuries to parenchymal and endothelial cells, which lead to hepatocyte cell death and sinusoidal dysfunction, activation of hepatic stellate cells and resident macrophages, and recruitment of other immune cells . Intercellular communication between parenchymal and nonparenchymal cells further contributes to progressive fibrogenesis and aggravates ACLD.…”

mentioning

confidence: 99%

“…Improvement of ACLD might be accomplished with the cessation of injury or by drug‐induced amelioration of hepatic cells . Unfortunately, current options to improve ACLD and its main clinical complications are limited, and although statins have shown beneficial effects on portal hypertension and survival, the risk reduction afforded by these and other agents is limited, indicating that new therapeutic strategies are warranted.…”

mentioning

confidence: 99%

“…(1,2) Progression of cirrhosis encompasses multiple coordinated cellular de-regulations, including initial injuries to parenchymal and endothelial cells, which lead to hepatocyte cell death and sinusoidal dysfunction, activation of hepatic stellate cells and resident macrophages, and recruitment of other immune cells. (3,4) Intercellular communication between parenchymal and nonparenchymal cells further contributes to progressive fibrogenesis and aggravates ACLD. Indeed, it has been described that, in response to injury, hepatocytes release damage-associated molecular patterns and other soluble and microencapsulated components that are able to affect neighboring cells.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

et al. 2019

View full text Add to dashboard Cite

In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De‐regulated inflammatory and pro‐apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan‐caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7‐day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl 4 administration. The hepato‐protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle‐treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. In vitro experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes’ expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. Conclusion : This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

et al. 2019

View full text Add to dashboard Cite

show abstract

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Pradhan

Banda

Farino

et al. 2020

Adv Healthcare Materials

View full text Add to dashboard Cite

The vascular system is integral for maintaining organ‐specific functions and homeostasis. Dysregulation in vascular architecture and function can lead to various chronic or acute disorders. Investigation of the role of the vascular system in health and disease has been accelerated through the development of tissue‐engineered constructs and microphysiological on‐chip platforms. These in vitro systems permit studies of biochemical regulation of vascular networks and parenchymal tissue and provide mechanistic insights into the biophysical and hemodynamic forces acting in organ‐specific niches. Detailed understanding of these forces and the mechanotransductory pathways involved is necessary to develop preventative and therapeutic strategies targeting the vascular system. This review describes vascular structure and function, the role of hemodynamic forces in maintaining vascular homeostasis, and measurement approaches for cell and tissue level mechanical properties influencing vascular phenomena. State‐of‐the‐art techniques for fabricating in vitro microvascular systems, with varying degrees of biological and engineering complexity, are summarized. Finally, the role of vascular mechanobiology in organ‐specific niches and pathophysiological states, and efforts to recapitulate these events using in vitro microphysiological systems, are explored. It is hoped that this review will help readers appreciate the important, but understudied, role of vascular‐parenchymal mechanotransduction in health and disease toward developing mechanotherapeutics for treatment strategies.

show abstract

Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury

et al. 2020

View full text Add to dashboard Cite

Background & Aims: Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well-understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single-cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis. Approach & Results: We applied single-cell transcriptomics to map the heterogeneity of sinusoid-associated cells in healthy and injured livers and reconstructed the singlelineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted Gene Co-Expression Network Analysis of the HSC trajectory led to the identification of core genes, whose expression proved highly predictive of advanced fibrosis in NASH patients. Among the core members of the injury-repressed gene module, we identified Plasmalemma vesicle-associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease. Conclusions: Our study offers a single-cell resolved account of drug-induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advance fibrosis in human NASH.

show abstract

Hepatic microcirculation and mechanisms of portal hypertension

Cited by 162 publications

References 213 publications

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury

Contact Info

Product

Resources

About