title: Initiation of acute graft-versus-host disease by angiogenesis.
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 with classical endothelial cell (EC) activation signs, such asVegfa/VEGFR1+2upregulation 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.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Riesner
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Biotechnology Center, and.
authors.forename: Angela
authors.initials: A
authors.lastname: Jacobi
authors.affiliation: University Clinic Carl Gustav Carus Dresden, Medical Clinic and Polyclinic 1, Technical University Dresden, Dresden, Germany; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Kräter
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kalupa
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Aleixandria
authors.initials: A
authors.lastname: McGearey
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mertlitz
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Cordes
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.|Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Jens-Florian
authors.initials: JF
authors.lastname: Schrezenmeier
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mengwasser
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Westphal
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Perez-Hernandez
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.|Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: Biotechnology Center, and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Guck
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2