Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia

Kashyap Krishnasamy, Anne Limbourg, Tamar Kapanadze, Jaba Gamrekelashvili, Christian Beger, Christine Häger, Vladimir J. Lozanovski, Christine S. Falk, L. Christian Napp, Johann Bauersachs, Matthias Mack, Hermann Haller, Christian Weber, Ralf H. Adams and Florian P. Limbourg ()
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Kashyap Krishnasamy: Hannover Medical School
Anne Limbourg: Hannover Medical School
Tamar Kapanadze: Hannover Medical School
Jaba Gamrekelashvili: Hannover Medical School
Christian Beger: Hannover Medical School
Christine Häger: Hannover Medical School
Vladimir J. Lozanovski: Hannover Medical School
Christine S. Falk: Hannover Medical School
L. Christian Napp: Hannover Medical School
Johann Bauersachs: Hannover Medical School
Matthias Mack: Uniklinikum
Hermann Haller: Hannover Medical School
Christian Weber: Ludwig-Maximilians-University
Ralf H. Adams: Max-Planck-Institute for Molecular Biomedicine, and University of Münster
Florian P. Limbourg: Hannover Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia.

Date: 2017
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DOI: 10.1038/s41467-017-00953-2

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