TY - JOUR
T1 - Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis
AU - Kantari-Mimoun, Chahrazade
AU - Castells, Magali
AU - Klose, Ralph
AU - Meinecke, Anna Katharina
AU - Lemberger, Ursula J.
AU - Rautou, Pierre Emmanuel
AU - Pinot-Roussel, Hélène
AU - Badoual, Cécile
AU - Schrödter, Katrin
AU - Österreicher, Christoph H.
AU - Fandrey, Joachim
AU - Stockmann, Christian
N1 - Publisher Copyright:
© 2014 by the American Association for the Study of Liver Diseases.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=84929606405&partnerID=8YFLogxK
U2 - 10.1002/hep.27635
DO - 10.1002/hep.27635
M3 - Article
C2 - 25475053
AN - SCOPUS:84929606405
SN - 0270-9139
VL - 61
SP - 2042
EP - 2055
JO - Hepatology
JF - Hepatology
IS - 6
ER -