Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

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.

Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty

“…Furthermore, the maximal expression of AT 2 R was found in developing fetal tissues, followed by an immediate reduction after birth and maintenance of relatively lower levels in adulthood ( Carey and Siragy, 2003 ). This was also confirmed by increased AT 1 R/AT 2 R expression ratios in aged animals ( Garcia-Garrote et al, 2019 ). This was attributed to age-associated changes in the distribution of Ang II receptors, with nuclear AT 1 Rs becoming the most common (85%) in older ages as opposed to nuclear AT 2 Rs being the most common (80%) at young ages ( Gwathmey et al, 2010 ).…”

“…This decrease was inhibited by treatment with the AT 1 R antagonist candesartan. Further, increased proliferation and generation of neuroblasts were shown in wild type mice with the administration of AT 2 R agonist C21 ( Garcia-Garrote et al, 2019 ). Similarly, it was shown that AT 1 R blockade can enhance hippocampal neurogenesis in hypertensive state ( Bhat et al, 2018 ; Drews et al, 2019 ).…”

Effect of angiotensin II and angiotensin‐(1–7) on proliferation of stem cells from human dental apical papilla

“…In addition, previous studies have provided strong evidence for Mas/AT2 heterodimerization and an interdependence in producing their physiological responses (Leonhardt et al, 2017). Interestingly, a functional dependence of AT2 receptor actions on Mas receptors was observed in neural stem cells proliferation of the adult rodent brain (Garcia‐Garrote et al, 2019). However, further studies are needed to assess the dimerization of angiotensin receptors specifically in SCAPs and how this could interfere with the proliferative pathway of these cells.…”

“…However, pre‐incubation the SCAPs with PD123319, an AT2 antagonist, attenuated the proliferative effect of Ang‐(1–7). A number of studies have shown the involvement of the AT2 receptor in the effects evoked by Ang‐(1–7) (Bosnyak et al, 2011; Castro et al, 2005; Garcia‐Garrote et al, 2019; Raffai & Lombard, 2016; Tesanovic, Vinh, Gaspari, Casley, & Widdop, 2010; Yousif et al, 2017). Although Ang‐(1–7) possess lower affinity for the AT2 receptor than Ang II, this heptapeptide presents substantial selectivity for AT2 (Bosnyak et al, 2011; Jones, Vinh, McCarthy, Gaspari, & Widdop, 2008; Walters, Gaspari, & Widdop, 2005).…”

“…However, both Ang II and Ang‐(1–7) can induce similar proliferative effects. Ang II has mitogenic effect in human lung fibroblasts (Marshall, McAnulty, & Laurent, 2000), epidermal stem cells (Liao et al, 2019), human cerebral artery smooth muscle cells (Z. Wang, Rao, Shillcutt, & Newman, 2005), proximal tubular epithelial cells (Cao et al, 2000), hematopoietic progenitor cells (Mrug, Stopka, Julian, Prchal, & Prchal, 1997) hippocampal neuronal stem cell (Chao, Yang, Buch, & Gao, 2013), and neurosphere‐forming cells from neural stem/progenitor stem cells (Garcia‐Garrote et al, 2019). Although studies have shown that Ang‐(1–7) have antiproliferative effects (Bihl et al, 2015; Domińska et al, 2018), this heptapeptide also presents proliferative effects in some cells, such as endothelial cell (Jiang et al, 2014), cardiac progenitor cells (Qi et al, 2013; Vasam et al, 2017), CD14 + cells (Heringer‐Walther et al, 2009), and in various hematopoietic pluripotent progenitors lineages after radiation exposure (Rodgers et al, 2012) or myelosuppression induced by chemotherapy (Rodgers, Espinoza, Roda, Meeks, & Dizerega, 2013).…”