Title

Role of regulator of G-protein signaling 5 protein in modulating emotional behaviors in the presence and absence of angiotensin 2-induced hypertension

Document Type

Conference Proceeding

Publication Date

4-20-2018

Abstract

Angiotensin II (Ang II), through its actions on the Ang II type 1 receptor, a G-protein coupled receptor (GPCR), increases blood pressure and causes oxidative stress and inflammation in multiple tissues, including in the cerebral vasculature. Ang II-induced brain inflammation may also contribute to emotional abnormalities, such as anxiety- and depression-like behavior. Regulator of G-protein signaling (RGS) proteins modulate responses to extracellular signals (such as Ang II) acting through GPCRs by accelerating GTPase activity on Gα subunits, thus terminating G-protein activity. RGS5, which is expressed in the brain and cerebral vasculature, mediates Ang II-induced increases in blood pressure and vascular structure. In this study, we examined the role of RGS5 in modulating cerebral vascular oxidative stress, and anxiety- and depression-like behavior in the absence and presence of elevated Ang II levels in adult (20–24 week old) male mice. Wild-type (RGS5+/+) and RGS5-deficient (RGS5−/−) mice were treated with vehicle (veh, saline) or Ang II (1 mg/kg/d) via osmotic minipumps for 21 days. Systolic blood pressure (SBP, measured using tail cuff), anxiety (measured using elevated plus maze) and depression (measured using tail suspension test)-related behaviors were assessed in conscious mice; superoxide levels (measured using LO12 chemiluminesence) were examined in isolated cerebral vessels. Ang II treatment caused a greater increase in SBP in RGS5−/− compared to RGS5+/+ mice (ΔSBP at Day 17 in Ang II–treated RGS5+/+= 16±7mmHg, n=10; Ang II-treated RGS5−/−= 37±5 mmHg, n=10, P<0.05), confirming that RGS5 modulates Ang II-induced increases in blood pressure. In RGS5+/+ mice, Ang II treatment increased anxiety-like behavior (time spent in open arms [secs] in veh-treated RGS5+/+=79±12, n=7; Ang II-treated=49±5, n=8, P<0.05). In vehicle-treated RGS5−/− mice, anxiety-like behavior was increased compared to vehicle-treated RGS5+/+ mice (time spent in open arms [secs] in veh-treated RGS5−/−=36±5, n=8, P<0.05 vs veh-treated RGS5+/+), suggesting that RGS5 deficiency causes anxiety-like behavior. There was no further effect of Ang II treatment on anxiety-like behavior in RGS5−/− mice (time spent in open arms [secs] in Ang II-treated RGS5−/−=44±7, n=9, P>0.05 vs veh-treated RGS−/−). Ang II treatment, and RGS5 deficiency alone had no effect on depression-like behavior (time immobilized [secs] in veh-treated RGS5+/+=164±10, n=11; Ang II-treated RGS5+/+=170±10, n=10, P>0.05 vs vehicle; veh-treated RGS5−/−=178±12, n=10, P>0.05 vs veh-treated RGS5+/+); however combined RGS5 deficiency and Ang II treatment resulted in an increase in depression-like behavior (time immobilized [secs] in Ang II-treated RGS5−/−=202±10, n=11, P<0.05 vs Ang II-treated RGS5+/+), suggesting that combined RGS5 deficiency and Ang II treatment increased depression-like behavior compared to Ang II treatment alone. There was no effect of Ang II treatment or RGS5 deficiency on cerebral vascular superoxide levels. Overall, these data suggest important roles for RGS5 in modulating Ang II-induced increases in blood pressure, and anxiety- and depression-like behavior.

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