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Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats.
- Source :
-
Gastroenterology [Gastroenterology] 2012 Apr; Vol. 142 (4), pp. 918-927.e6. Date of Electronic Publication: 2011 Dec 16. - Publication Year :
- 2012
-
Abstract
- Background & Aims: Capillarization, characterized by loss of differentiation of liver sinusoidal endothelial cells (LSECs), precedes the onset of hepatic fibrosis. We investigated whether restoration of LSEC differentiation would normalize crosstalk with activated hepatic stellate cells (HSC) and thereby promote quiescence of HSC and regression of fibrosis.<br />Methods: Rat LSECs were cultured with inhibitors and/or agonists and examined by scanning electron microscopy for fenestrae in sieve plates. Cirrhosis was induced in rats using thioacetamide, followed by administration of BAY 60-2770, an activator of soluble guanylate cyclase (sGC). Fibrosis was assessed by Sirius red staining; expression of α-smooth muscle actin was measured by immunoblot analysis.<br />Results: Maintenance of LSEC differentiation requires vascular endothelial growth factor-A stimulation of nitric oxide-dependent signaling (via sGC and cyclic guanosine monophosphate) and nitric oxide-independent signaling. In rats with thioacetamide-induced cirrhosis, BAY 60-2770 accelerated the complete reversal of capillarization (restored differentiation of LSECs) without directly affecting activation of HSCs or fibrosis. Restoration of differentiation to LSECs led to quiescence of HSCs and regression of fibrosis in the absence of further exposure to BAY 60-2770. Activation of sGC with BAY 60-2770 prevented progression of cirrhosis, despite continued administration of thioacetamide.<br />Conclusions: The state of LSEC differentiation plays a pivotal role in HSC activation and the fibrotic process.<br /> (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Actins metabolism
Animals
Benzoates pharmacology
Biphenyl Compounds
Blotting, Western
Capillaries drug effects
Capillaries metabolism
Cell Proliferation
Cells, Cultured
Cyclic GMP metabolism
Disease Progression
Endothelial Cells drug effects
Endothelial Cells metabolism
Enzyme Activation
Enzyme Activators pharmacology
Guanylate Cyclase metabolism
Hepatic Stellate Cells drug effects
Hepatic Stellate Cells metabolism
Hydrocarbons, Fluorinated pharmacology
Liver drug effects
Liver metabolism
Liver Cirrhosis, Experimental chemically induced
Liver Cirrhosis, Experimental metabolism
Liver Cirrhosis, Experimental prevention & control
Male
Microscopy, Electron, Scanning
Nitric Oxide
Phenotype
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear metabolism
Signal Transduction
Soluble Guanylyl Cyclase
Thioacetamide
Vascular Endothelial Growth Factor A metabolism
Capillaries pathology
Cell Differentiation drug effects
Endothelial Cells pathology
Hepatic Stellate Cells pathology
Liver blood supply
Liver pathology
Liver Cirrhosis, Experimental pathology
Paracrine Communication drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 142
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 22178212
- Full Text :
- https://doi.org/10.1053/j.gastro.2011.12.017