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The role of receptor MAS in microglia-driven retinal vascular development

Authors

  • S. Foulquier
  • V. Caolo
  • G. Swennen
  • I. Milanova
  • S. Reinhold
  • C. Recarti
  • N. Alenina
  • M. Bader
  • U M. Steckelings
  • T. Vanmierlo
  • M.J. Post
  • E.A. Jones
  • R.J. van Oostenbrugge
  • T. Unger

Journal

  • Angiogenesis

Citation

  • Angiogenesis

Abstract

  • Objective The receptor MAS, encoded by Mas1, is expressed in microglia and its activation has been linked to anti-infammatory actions. However, microglia are involved in several diferent processes in the central nervous system, including the promotion of angiogenesis. We therefore hypothesized that the receptor MAS also plays a role in angiogenesis via microglia. Approach and results To assess the role of MAS on vascular network development, fat-mounted retinas from 3-day-old wild-type (WT) and Mas1−/− mice were subjected to Isolectin B4 staining. The progression of the vascular front was reduced (− 24%, p<0.0001) and vascular density decreased (− 38%, p <0.001) in Mas1−/− compared to WT mice with no change in the junction density. The number of flopodia and flopodia bursts were decreased in Mas1−/− mice at the vascular front (− 21%, p <0.05; − 29%, p<0.0001, respectively). This was associated with a decreased number of vascular loops and decreased microglial density at the vascular front in Mas1−/− mice (-32%, p<0.001; − 26%, p<0.05, respectively). As the front of the developing vasculature is characterized by reduced oxygen levels, we determined the expression of Mas1 following hypoxia in primary microglia from 3-day-old WT mice. Hypoxia induced a 14-fold increase of Mas1 mRNA expression (p<0.01). Moreover, stimulation of primary microglia with a MAS agonist induced expression of Notch1 (+57%, p <0.05), Dll4 (+220%, p <0.001) and Jag1 (+137%, p <0.001), genes previously described to mediate microglia/endothelial cell interaction during angiogenesis. Conclusions: Our study demonstrates that the activation of MAS is important for microglia recruitment and vascular growth in the developing retina.


DOI

doi:10.1007/s10456-019-09671-3