Estrogen treatment restores perivascular adipose tissue -mediated anticontractile effect via NOX4-dependent hydrogen peroxide signaling in ovariectomized hypertensive rats

Introduction/aim: Reduced endogenous estrogen increases NADPH oxidase-derived reactive oxygen species (ROS) and promotes vascular dysfunction. Although estrogen treatment restores vascular redox balance, its direct impact on perivascular adipose tissue (PVAT) function in hypertension remains unclear. We tested the hypothesis that estrogen attenuates vascular contraction in ovariectomized spontaneously hypertensive rats (SHR) by enhancing NOX4-derived hydrogen peroxide (H 2 O 2 ) signaling in PVAT. Material and methods: Vascular reactivity, western blotting, RT- PCR, and H 2 O 2 levels were performed in PVAT SHR from Sham (intact females), OVX (ovariectomized), and Estrogen (OVX treated with 17β-estradiol). Results: The anticontractile effect of PVAT was abolished in arteries from OVX rats and fully restored by estrogen treatment. Pharmacological inhibition of NOX4 significantly enhanced phenylephrine-induced contraction in arteries with PVAT from estrogen-treated rats, indicating a functional role for NOX4 signaling. H 2 O 2 levels were markedly reduced in PVAT from OVX rats and restored to sham levels following estrogen replacement. Consistently, NOX4 protein and mRNA levels were decreased in PVAT from OVX SHR and normalized by estrogen treatment. Conclusion: Estrogen positively modulates PVAT anticontractile effect in mesenteric resistance arteries through mechanisms dependent on NOX4 and H 2 O 2 levels. These findings identify NOX4/H 2 O 2 as a key estrogen-sensitive regulator of PVAT and vascular tone.