title: Boosting the hypoxic response in myeloid cells accelerates resolution of fibrosis and regeneration of the liver in mice.
abstract: We have recently shown that targeting Vascular Endothelial Growth Factor (VEGF) specifically in scar-infiltrating myeloid cells prevented remodeling of the sinusoidal vasculature and abrogated the resolution of murine liver fibrosis, thereby unmasking an unanticipated link between angiogenesis and resolution of fibrosis. In a gain of function approach, we wanted to test the impact of VEGF overexpression in myeloid cells on fibrolysis. We observe that genetic inactivation of the von Hippel Lindau protein (VHL), a negative regulator of Hypoxia-inducible factors (HIF) in myeloid cells, leads to increased VEGF expression and most importantly, accelerated matrix degradation and reduced myofibroblast numbers after CCl4 challenge. This is associated with enhanced expression of MMP-2 and -14 as well as lower expression of TIMP-2 in liver endothelial cells. In addition, we report increased expression of MMP-13 in scar-associated macrophages as well as improved liver regeneration upon ablation of VHL in myeloid cells. Finally, therapeutic infusion of macrophages nulli-zygous for VHL or treated with the pharmacologic hydroxylase inhibitor and HIF-inducer Dimethyloxalylglycine (DMOG) accelerates resolution of fibrosis. Hence, boosting the HIF-VEGF signaling axis in macrophages represents a promising therapeutic avenue for the treatment of liver 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: Ewelina
authors.initials: E
authors.lastname: Krzywinska
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: Corinne
authors.initials: C
authors.lastname: Milien
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, Germany.
authors.forename: Anna-Katharina
authors.initials: AK
authors.lastname: Meinecke
authors.affiliation: Division of Gastroenterology and Hepatology Department of Medicine III Medical University of Vienna, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Lemberger
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Milos
authors.initials: M
authors.lastname: Gojkovic
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schrödter
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Österreicher
authors.affiliation: Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Rundqvist
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; D017209:Apoptosis; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C507096:Mmp14 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D053511:Matrix Metalloproteinase 14; C494469:VHL protein, mouse
keywords: fibrolysis; liver fibrosis; matrix metalloproteinases; scar-associated macrophage; vascular endothelial growth factor