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

Angiogenesis. 2019 Nov;22(4):481-489. doi: 10.1007/s10456-019-09671-3. Epub 2019 Jun 20.

Abstract

Objective: The receptor MAS, encoded by Mas1, is expressed in microglia and its activation has been linked to anti-inflammatory actions. However, microglia are involved in several different 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, flat-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 filopodia and filopodia 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.

Keywords: Angiogenesis; Angiotensin receptors; CNS; Developmental biology; Endothelium; Macrophage; Renin angiotensin system; Vascular biology.

MeSH terms

  • Animals
  • Cell Hypoxia
  • Gene Expression Regulation*
  • Mice
  • Mice, Knockout
  • Microglia / metabolism*
  • Microglia / pathology
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Receptors, G-Protein-Coupled / biosynthesis*
  • Receptors, G-Protein-Coupled / genetics
  • Retina / metabolism*
  • Retina / pathology
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism*
  • Retinal Neovascularization / pathology
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology

Substances

  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1