Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Peripheral Vascular Disease, Cardiovascular System & Cardiology, Angiogenesis, Renin angiotensin system, Angiotensin receptors, Macrophage, CNS, Developmental biology, Endothelium, Vascular biology, RENIN-ANGIOTENSIN SYSTEM, RAT-BRAIN, MATRIX-METALLOPROTEINASE, CANCER XENOGRAFTS, ANGIOGENESIS, EXPRESSION, GROWTH, HEALTH, ADULT, CELLS, Animals, Cell Hypoxia, Gene Expression Regulation, Mice, Mice, Knockout, Microglia, Proto-Oncogene Mas, Proto-Oncogene Proteins, Receptors, G-Protein-Coupled, Retina, Retinal Neovascularization, Retinal Vessels, 1103 Clinical Sciences, 1115 Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology

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.