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

Abstract

ObjectiveThe 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 resultsTo 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.ConclusionsOur study demonstrates that the activation of MAS is important for microglia recruitment and vascular growth in the developing retina.Electronic supplementary materialThe online version of this article (10.1007/s10456-019-09671-3) contains supplementary material, which is available to authorized users.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…In particular, TGF-β, which is a target molecule of stroma normalization, can affect immunotherapy through many mechanisms, such as the intratumoral distribution of T cells (18,65). Indeed, stroma-normalizing mechanotherapeutic drugs might have the capacity to directly act on immune and endothelial cells (66)(67)(68). Another process not included in the model is the delivery of ICB antibodies from the bloodstream into the tumor; instead, we model their activity, the lack of dependence of T-cell infiltration from VEGF levels, and the repulsion of T cells from cancer cells via CXCR4 signaling, and we assume that migration rates of T cells do not depend on oxygen levels.…”

Vessel-Associated Immune Cells in Cerebrovascular Diseases: From Perivascular Macrophages to Vessel-Associated Microglia

“…Once microglia encounter harmful substances, such as infiltrating components from blood, burden abnormal proteins, or cell debris, they become activated to phagocyte these harmful substances or to protect the damaged cells (Hu et al, 2015). Furthermore, microglia can promote angiogenesis in both physiological (Foulquier et al, 2019) and pathological conditions such as ischemic stroke, AD, multiple sclerosis (MS), and Parkinson’s disease (PD) (Zhao et al, 2018), highlighting the important cross-talk of microglia with the cerebral vasculature (VAM). There is, however, a lack of molecular studies to differentiate VAM from the general population of parenchymal microglia, and we suggest that an advanced molecular characterization should be undertaken to reveal their true nature and assess their potential protective and/or deleterious functions in the context of cerebrovascular diseases.…”

The Contribution of Microglia to the Development and Maturation of the Visual System

“…With respect to the exact mechanism of this microglial mediation of vascular growth, the chemokine receptor CX3CR1, which is primarily expressed by microglia in the healthy CNS, has been shown to mediate endothelial cell migration and tube formation in cell culture (Volin et al, 2001). A more recent study has shown that genetic deletion of the Angiotensin (1-7) receptor MAS (Mas1 −/− ), resulted in impaired retinal vascular development due to reduced microglial number at the developing vascular front (Foulquier et al, 2019). Interestingly, the activation of MAS upregulates the Notch signaling pathway, which has been linked to microglial localization and interaction with endothelial cells within the retina (Foulquier et al, 2019;Haupt et al, 2019).…”

“…A more recent study has shown that genetic deletion of the Angiotensin (1-7) receptor MAS (Mas1 −/− ), resulted in impaired retinal vascular development due to reduced microglial number at the developing vascular front (Foulquier et al, 2019). Interestingly, the activation of MAS upregulates the Notch signaling pathway, which has been linked to microglial localization and interaction with endothelial cells within the retina (Foulquier et al, 2019;Haupt et al, 2019).…”