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Der Einfluss der Gefäßremodellierung auf die Entstehung und Rückbildung von Gewebsfibrosen

Meinecke, Anna-Katharina

Fibrosis is a pathological process with limited therapeutic options that can occur in almost every tissue or organ of the body. Among others, pulmonary fibrosis and liver fibrosis are two increasingly important fibrotic diseases worldwide. Both are characterized by an increased accumulation of myofibroblasts and an excessive deposition of matrix proteins, mostly collagen. These processes lead to scar formation and the destruction of the organ. Furthermore lung and liver fibrosis are associated with an extensive remodeling of the blood and the lymphatic vasculature, though the impact of vascular remodeling on the development and regression of tissue fibrosis is still a matter of debate. Numerous Papers deal with the role of hemangiogenesis in pulmonary fibrosis, yet the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains to be elucidated. In a murine model of pulmonary fibrosis we show that lymphatics exhibit ectopic mural cell coverage. Lymphatic endothelial cells in fibrotic lungs showed an increased expression of platelet-derived growth factor B (PDGF-B), which led to the recruitment of platelet-derived growth factor receptor-β (PDGFR-β)-expressing mural cells. This abnormal lymphatic vascular pattern in fibrotic lungs caused impaired lymphatic drainage and led to a perilymphatic accumulation of fibrogenic molecules. The pharmacological inhibition of the PDGF-B/PDGFR-β-signaling at the onset of mural cell recruitment prevented mural cell recruitment to lymphatics and restored the transport capacity of the lymphatic vessels. The second part of this thesis investigates the impact of vascular remodeling on liver fibrosis. To date there is no clear evidence whether angiogenesis is a pro- or antifibrotic mediator in liver fibrosis. Furthermore, although liver fibrosis is known to be reversible, the role of hemangiogenesis in the regression of liver fibrosis has not been studied yet. Macrophages are a major source of VEGF-A (VEGF), the most important angiogenic transcription factor. To address the question how hemangiogenesis is affected by macrophage-derived VEGF in liver fibrosis and to determine its impact on the regression of liver fibrosis, we used a murine knockout model for myeloid cell-derived VEGF. We were able to show that myeloid cell-derived VEGF is a major VEGF-source during the resolution of liver fibrosis. Mice that lack myeloid cell-derived VEGF were not able to resolve liver fibrosis. VEGF-deficient mice showed lower expression and activity of matrix metalloproteinases (MMP) and liver sinusoids failed to migrate into fibrotic areas. The reintroduction of myeloid cell-derived VEGF prior to the recovery phase by means of bone marrow transplantation led to an increase in MMP-expression and -activity and resulted in increased collagen degradation. Hence liver sinusoids entered perisinusoidal and pericentral fibrotic areas and supported the regression of the liver fibrosis.

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Meinecke, Anna-Katharina: Der Einfluss der Gefäßremodellierung auf die Entstehung und Rückbildung von Gewebsfibrosen. 2013.

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