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Angiogenesis. 2019 Jun 20. doi: 10.1007/s10456-019-09671-3. [Epub ahead of print]

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

Author information

1
Department of Pharmacology-Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. s.foulquier@maastrichtuniversity.nl.
2
Cardiovascular Research Institute Maastricht, CARIM, Maastricht, The Netherlands. s.foulquier@maastrichtuniversity.nl.
3
MH&NS, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. s.foulquier@maastrichtuniversity.nl.
4
Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
5
Department of Physiology, Maastricht University, Maastricht, The Netherlands.
6
Cardiovascular Research Institute Maastricht, CARIM, Maastricht, The Netherlands.
7
Department of Pharmacology-Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
8
Department of Molecular Cell Biology, Maastricht University, Maastricht, The Netherlands.
9
Max Delbruck Center for Molecular Medicine, Berlin, Germany.
10
Partner Site Berlin, DZHK (German Center for Cardiovascular Research), Berlin, Germany.
11
Berlin Institute of Health (BIH), Berlin, Germany.
12
Charité - University Medicine, Berlin, Germany.
13
Institute for Biology, University of Lübeck, Lübeck, Germany.
14
Institute of Molecular Medicine, Department of Cardiovascular & Renal Research, University of Southern Denmark, Odense, Denmark.
15
Department of Immunology and Biochemistry, Biomed, Hasselt University, Diepenbeek, Belgium.
16
MH&NS, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
17
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

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

PMID:
31240418
DOI:
10.1007/s10456-019-09671-3

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