Estrogen Receptor-β in the Paraventricular Nucleus and Rostroventrolateral Medulla Plays an Essential Protective Role in Aldosterone/Salt-Induced Hypertension in Female Rats

The identification of the specific estrogen receptor (ER) subtypes that are involved in estrogen protection from hypertension and their specific locations in the central nervous system is critical to our understanding and design of effective estrogen replacement therapies in women. Using selective ER agonists and recombinant adeno-associated virus (AAV) carrying small interference (si) RNA to silence either ER alpha (AAV-siRNA-ER alpha) or ER beta (AAV-siRNA-ER beta), the present study investigated regional specificity of different ER subtypes in the protective actions of estrogen in aldosterone (Aldo)-induced hypertension. Intracerebroventricular infusions of either diarylpropionitrile, a selective ER beta agonist, or propyl-pyrazole-triol, a selective ER alpha agonist, attenuated Aldo/NaCl-induced hypertension in ovariectomized rats. In contrast, intracerebroventricular injections of siRNA-ER alpha or siRNA-ER beta augmented Aldo-induced hypertension in intact females. Site-specific paraventricular nucleus (PVN) or rostroventrolateral medulla (RVLM) injections of siRNA-ER beta augmented Aldo-induced hypertension. However, rats with PVN or RVLM injections of siRNA-ER alpha did not significantly increase blood pressure induced by Aldo. Real-time polymerase chain reaction analyses of the PVN and RVLM of siRNA-injected rat confirmed a marked reduction in the expression of ER alpha and ER beta. In cultured PVN neurons, silencing either ER alpha or ER beta by culturing PVN neurons with siRNA-ER alpha or siRNA-ER beta enhanced Aldo-induced reactive oxygen species production. Ganglionic blockade after Aldo infusion showed an increase in sympathetic activity in ERa knockdown rats. These results indicate that both PVN and RVLM ER beta, but not ER alpha in these nuclei, contribute to the protective effects of estrogen against Aldo-induced hypertension. The brain regions responsible for the protective effects of estrogen interaction with ER alpha in Aldo-induced hypertension still need to be determined.