Research Papers:
Boosting the hypoxic response in myeloid cells accelerates resolution of fibrosis and regeneration of the liver in mice
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Abstract
Chahrazade Kantari-Mimoun1,*, Ewelina Krzywinska1,*, Magali Castells1, Corinne Milien1, Ralph Klose1, Anna-Katharina Meinecke2, Ursula Lemberger3, Thomas Mathivet1, Milos Gojkovic4, Katrin Schrödter2, Christoph Österreicher5, Joachim Fandrey2, Helene Rundqvist4, Christian Stockmann1
1Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France
2Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Germany
3Division of Gastroenterology and Hepatology Department of Medicine III Medical University of Vienna, Austria
4Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
5Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna, Austria
*These authors contributed equally to this work
Correspondence to:
Christian Stockmann, email: [email protected]
Keywords: liver fibrosis, vascular endothelial growth factor, scar-associated macrophage, matrix metalloproteinases, fibrolysis
Received: August 26, 2016 Accepted: January 10, 2017 Published: January 19, 2017
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.
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