title: Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles.
abstract: Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC-derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1-immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1-expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF-conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A-containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells.
  
  
  CONCLUSIONS
  PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA-laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma.
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, CDR Saint-Antoine and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; INSERM, UMR_S 938, Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Lemoinne
authors.forename: Axelle
authors.initials: A
authors.lastname: Cadoret
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Rautou
authors.forename: Haquima
authors.initials: H
authors.lastname: El Mourabit
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.forename: Christophe
authors.initials: C
authors.lastname: Corpechot
authors.forename: Colette
authors.initials: C
authors.lastname: Rey
authors.forename: Nelly
authors.initials: N
authors.lastname: Bosselut
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.forename: Gérard
authors.initials: G
authors.lastname: Feldmann
authors.forename: Chantal
authors.initials: C
authors.lastname: Boulanger
authors.forename: Corneliu
authors.initials: C
authors.lastname: Henegar
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
mesh_terms: D000818:Animals; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003094:Collagen / Q000032:analysis; D006801:Humans; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008297:Male; D058628:Myofibroblasts / Q000502:physiology*; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D066253:Vascular Remodeling
chemical_list: C085811:COL15A1 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen