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Initiation of acute graft-versus-host disease by angiogenesis

Official URL:https://doi.org/10.1182/blood-2016-08-736314
PubMed:View item in PubMed
Creators Name:Riesner, K. and Shi, Y. and Jacobi, A. and Kraeter, M. and Kalupa, M. and McGearey, A. and Mertlitz, S. and Cordes, S. and Schrezenmeier, J.F. and Mengwasser, J. and Westphal, S. and Perez-Hernandez, D. and Schmitt, C. and Dittmar, G. and Guck, J. and Penack, O.
Journal Title:Blood
Journal Abbreviation:Blood
Page Range:2021-2032
Date:6 April 2017
Keywords:Acute Disease, Allografts, Animal Disease Models, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Inflammatory Bowel Diseases, Pathologic Neovascularization, Transgenic Mice, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Animals, Mice
Abstract:The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, it is not known if angiogenesis has an active role during the initiation of inflammation or if it is merely a secondary effect occurring in response to stimuli by tissue infiltrating leukocytes. Here we show that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and acute graft-versus-host disease (GVHD). We found that angiogenesis occurred as early as day+2 after allogeneic transplantation mainly in GVHD typical target organs skin, liver and intestines whereas no angiogenic changes appeared due to conditioning or syngeneic transplantation. The initiation phase of angiogenesis was not associated to classical endothelial cell (EC) activation signs, such as Vegfa/VEGFR1+2 upregulation or increased adhesion molecule expression. During early GVHD at day+2, we found significant metabolic and cytoskeleton changes in target organ ECs in gene array- and proteomic analyses. These modifications have significant functional consequences as indicated by profoundly higher deformation in Real-time deformability cytometry. Our results demonstrate that metabolic changes trigger alterations in cell mechanics leading to enhanced migratory and proliferative potential of ECs during the initiation of inflammation. Our study adds evidence to the hypothesis that angiogenesis is involved in the initiation of tissue inflammation during GVHD.
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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