Regulator of G-Protein Signaling 5 Protein Deficiency Differentially Influences Blood Pressure, Vascular and Behavioral Effects in Aged Male Mice

Aging and elevated activity of the renin-angiotensin-system (RAS) are associated with hypertension, vascular and emotional behavioral abnormalities, like anxiety and depression. Many actions of the main effector hormone of the RAS, angiotensin II (Ang II), are mediated by Ang II type 1 receptor whose activity is modulated by the regulator of G-protein signaling 5 (RGS5) protein. We assessed the role of RGS5 on blood pressure, vascular and emotional behavioral outcomes in aged male mice in the presence and absence of chronically elevated Ang II levels. We used aged (∼21-month old) male RGS5-deficient (RGS5 -/- ) and wild-type (RGS5 +/+ ) mice treated with vehicle (saline) or Ang II (1 mg/kg/d for 21 days). RGS5 deficiency increased baseline and cerebral vascular superoxide levels in the presence of chronically elevated Ang II levels, suggesting that RGS5 deficiency leads to elevated blood pressure and deleterious cerebral vascular outcomes in aged mice. RGS5 deletion had no effect on Ang II-induced increases in systolic blood pressure. Chronically elevated Ang II levels increased spontaneous locomotor activity in RGS5 +/+ but not RGS5 -/- mice. RGS5 deficiency and Ang II treatment had no effect on anxiety- and depression-like behavior. This is the first study to assess the effects of deficiency of an RGS protein in the vasculature or on emotional behavioral outcomes in aged mice. We report that RGS5 has protective effects on blood pressure and the cerebral vasculature in aged mice. Clinically, these data suggest that RAS blockers may significantly reduce cerebrovascular disease risk in aged males lacking RGS5.