title: Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis.
abstract: Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic liver and can profoundly contribute to remodeling of liver sinusoids. We observe that the development of fibrosis is associated with decreased hepatic vascular endothelial growth factor (VEGF) expression as well as sinusoidal rarefication of the fibrotic scar. In contrast, the resolution of fibrosis is characterized by a rise in hepatic VEGF levels and revascularization of the fibrotic tissue. Genetic ablation of VEGF in myeloid cells or pharmacological inhibition of VEGF receptor 2 signaling prevents this angiogenic response and the resolution of liver fibrosis. We observe increased expression of matrix metalloproteases as well as decreased expression of tissue inhibitor of metalloproteases confined to sinusoidal endothelial cells in response to myeloid cell VEGF. Remarkably, reintroduction of myeloid cell-derived VEGF upon recovery restores collagenolytic acitivity and the resolution of fibrosis.
  
  
  CONCLUSIONS
  We identify myeloid cell-derived VEGF as a critical regulator of extracellular matrix degradation by liver endothelial cells, thereby unmasking an unanticipated link between angiogenesis and the resolution of fibrosis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Chahrazade
authors.initials: C
authors.lastname: Kantari-Mimoun
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Castells
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Ralph
authors.initials: R
authors.lastname: Klose
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Meinecke
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ursula J
authors.initials: UJ
authors.lastname: Lemberger
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.|DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Rautou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.|Service d'Anatomie et Pathologie, Hôpital Européen Georges Pompidou, APHP, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Pinot-Roussel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.|Service d'Anatomie et Pathologie, Hôpital Européen Georges Pompidou, APHP, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schrödter
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Österreicher
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Duisburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000201:enzymology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000473:pathology / Q000502:physiology*; D008103:Liver Cirrhosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology*; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A