title: Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
  
  
  CONCLUSIONS
  The state of LSEC differentiation plays a pivotal role in HSC activation and the fibrotic process.
authors.affiliation: Division of Gastrointestinal and Liver Disease, University of Southern California Research Center for Liver Disease, Los Angeles, California 90033, USA.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Roscoe D
authors.initials: RD
authors.lastname: Atkinson
authors.forename: Gary C
authors.initials: GC
authors.lastname: Kanel
authors.forename: William A
authors.initials: WA
authors.lastname: Gaarde
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Deleve
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D008855:Microscopy, Electron, Scanning; D009569:Nitric Oxide; D019899:Paracrine Communication / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013853:Thioacetamide; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000199:Actins; D001565:Benzoates; D001713:Biphenyl Compounds; D006152:Cyclic GMP; D020536:Enzyme Activators; D006162:Guanylate Cyclase; D006845:Hydrocarbons, Fluorinated; D009569:Nitric Oxide; D018160:Receptors, Cytoplasmic and Nuclear; D000071756:Soluble Guanylyl Cyclase; D013853:Thioacetamide; D042461:Vascular Endothelial Growth Factor A; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; C498862:Acta2 protein, rat; C467498:vascular endothelial growth factor A, rat