Abstract
The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.
Highlights
New neurons destined to integrate into olfactory bulb (OB) circuits are continuously generated from neural stem cells (NSCs) in the ventricular–subventricular zone (V-SVZ) of the lateral ventricles in the adult rodent brain
Actions in neurospheres, we seeded single cells dissociated from neurospheres in medium with and without 100 nM angiotensin II (Ang II) combined with concurrent administration of Ang IIII type-1 type-1 (AT1) and angiotensin type-2 receptors (AT2) receptor antagonists, 1 μM
The results show that AT1 and AT2 receptors played a major role in NSC proliferation and/or generation of neuroblasts in the V-SVZ
Summary
New neurons destined to integrate into olfactory bulb (OB) circuits are continuously generated from neural stem cells (NSCs) in the ventricular–subventricular zone (V-SVZ) of the lateral ventricles in the adult rodent brain. These self-renewing NSCs exhibit features that are typical of mature astroglial. Cells 2019, 8, 1551 or fetal radial glial cells, such as expression of glial fibrillary acidic protein (GFAP), and produce transit-amplifying neural progenitor cells (NPCs) These NPCs lack self-renewal and divide a few times before they commit to differentiate into doublecortin (DCX)-positive migrating neuroblasts, which migrate anteriorly and terminally differentiate in the OB [1,2]. Because endogenous NSCs appear to harness the potential to repair lesioned circuits, the identification of signals and mechanisms that could stimulate NSC activity in the elderly is relevant
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