Natalia M. Mathieu, Pablo Nakagawa, Patricia Muskus, Daniel T. Brozoski, Justin L. Grobe, and Curt D. SigmundDepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI
The brain renin angiotensin system (RAS) is known for its role in cardiovascular and metabolic regulation. Angiotensin II (Ang II) is the major active product of the RAS, exerting most of its physiological effects through the angiotensin type-1 receptor (AT1R). Canonical or G proteinmediated signaling of the AT1R within the brain is known to induce dipsogenic and pressor responses to Ang II stimulation. Non-canonical or β-arrestin mediated signaling is thought to counterbalance the detrimental effects of canonical signaling. However, the role of the noncanonical AT1R/β-arrestin pathway within the brain is understudied. Therefore, we hypothesized that β-Arrestin activation within the brain contributes to blood pressure (BP) regulation. Global βarrestin1 (Arrb1) and β-arrestin2 (Arrb2) knockout (KO) mice were employed to evaluate BP upon treatment with 1) deoxycorticosterone acetate (DOCA)-salt and 2) Ang II. Age- and sex-matched C57BL/6J mice served as controls. First, mice were instrumented with radiotelemetry implants and BP was continuously recorded. At baseline, Arrb2-KO mice exhibited similar BP when compared to WT (WT=128±5.5 vs Arrb2-KO=131±5.4 mmHg; n=8 and 9, respectively). However. Arrb2-KO mice exhibited exacerbated responses to DOCA-salt compared to WT (WT=152±12 vs Arrb2-KO=163±10 mmHg; n=8 and 9, respectively; p=0.03). Second, BP was evaluated upon acute intracerebroventricular (ICV) injection of Ang II (1ug). Arrb-2KO mice showed a higher BP response to Ang II compared to WT (WT=144±17 vs Arrb2-KO=168±11 mmHg; n=8 and 9, respectively). These findings suggest that activation of β-arrestin2 might counterbalance the effects of canonical activation of the AT1R through G proteins. Overall, β-arrestin2 in the brain appears to protect against cardiovascular diseases since the genetic ablation of β-Arrestin2 resulted in an exacerbated BP, particularly with brain-specific injection of Ang II.