cFos-mediated β-Arrestin1 in the RVLM alleviates sympathetic hyperactivity induced by ovariectomy

Sympathetic hyperactivity is a key feature of cardiovascular dysfunction in postmenopausal women and is closely linked to the onset, progression, and outcomes of cardiovascular events. However, the mechanisms underlying sympathetic nerve hyperactivity due to menopause remain unclear. β-arrestin is a versatile class of intracellular proteins that were initially discovered for their ability to disrupt the G protein-coupled receptors (GPCRs) signaling by binding to activated receptors. A notable reduction in the expression of β-arrestin1 in the rostral ventrolateral medulla (RVLM) associated with increased sympathetic activity and elevated blood pressure (BP) in spontaneously hypertensive rats. It has been reported that the cellular oncogene fos (cFos), as a transcription factor, plays a crucial role in BP regulation. This study aimed to investigate whether β-arrestin1, regulated by cFos in the RVLM, contributes to sympathetic hyperactivity induced by menopause. Bilateral ovariectomy (OVX) was performed to establish a postmenopausal rat model. We found that the expression of β-arrestin1 in the RVLM of OVX rats was reduced, whereas estrogen supplementation increased the expression of β-arrestin1. Furthermore, overexpression of β-arrestin1 in the RVLM of OVX rats attenuated the sympathetic hyperactivity. Conversely, reducing β-arrestin1 expression in the RVLM compromised the cardioprotective effects of estrogen in OVX rats. Additionally, inhibiting the expression of the transcription factor cFos in the RVLM of OVX rats diminished the estrogen-induced increase in the expression of β-arrestin1. These findings suggest that estrogen enhances the expression of β-arrestin1 mediated by cFos in the RVLM of OVX rats, thereby alleviating sympathetic nerve hyperactivity and hypertension.