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Initiation of acute graft-versus-host disease by angiogenesis

Katarina Riesner, Yu Shi, Angela Jacobi, Martin Kräter, Martina Kalupa, Aleixandria McGearey, Sarah Mertlitz, Steffen Cordes, Jens-Florian Schrezenmeier, Jörg Mengwasser, Sabine Westphal, Daniel Perez-Hernandez, Clemens Schmitt, Gunnar Dittmar, Jochen Guck and Olaf Penack

Key Points

  • Angiogenesis preceded infiltration of inflammatory leukocytes during GVHD as well as during experimental colitis.

  • Metabolic alterations and cytoskeleton changes occurred during early angiogenesis, but classical endothelial activation signs were absent.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

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 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.

  • Submitted August 25, 2016.
  • Accepted January 8, 2017.
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