Identification of an Angiotensin-(1–7)-Producing fusion protein in the brain of transgenic rats Reveals a hypotensive effect mediated through modulation of the GABA–nNOS–NO pathway and highlighting Astrocyte–Neuron crosstalk

This study explores the anatomical distribution of Angiotensin-(Ang)-(1-7) fusion protein within the central nervous system of the novel transgenic rat model (TG7371). The Ang-(1-7)/Mas pathway of the renin-angiotensin system (RAS) plays a key role in cardiovascular regulation and influences higher brain functions, including cognition and emotion. TG7371 expresses a transgenic Ang-(1-7)-producing fusion protein which resulted in a hypotensive phenotype. Here, we assessed the expression of Ang-(1-7) fusion mRNA and protein in primary cortical cells from neonates and identified their distribution in the brain of adult rats using qPCR, WB, ISH, and immunolabeling. In neonates, Ang-(1-7) mRNA was mainly found in proliferating cells, whereas in adults, it was primarily identified in GFAP-positive astrocytes. The Ang-(1-7) fusion protein, however, was predominantly found in neurons, including GABAergic interneurons and specific pyramidal cells. High protein levels were particularly noted in cardiovascular control regions like the medulla, as well as in other non-cardiovascular areas. TG7371 displayed twofold increase in brain levels of Ang-(1-7) compared to Ang II vs. Control, which remained unchanged, alongside significant changes in the expression of RAS components and nNOS. These findings indicate that the Ang-(1-7) fusion protein modulates the GABA-nNOS-NO-pathway, contributing to the low blood pressure phenotype of these rats, and promotes a mode of astrocytes-neurons-communication. The widespread expression of the fusion protein in the brain also suggests a potential role in modulating mood, cognition, and neurological disorders. Overall, TG7371 presents a valuable model to explore the long-term cardiovascular and neurobehavioral effects of Ang-(1-7), highlighting promising therapeutic implications and neural crosstalk.