Effects of 17β estradiol on blood pressure elevation in ovariectomized rats with collagen-induced arthritis via modulation of oxidative stress, inflammation, fibrosis, and apoptosis in the aorta involving TLR4/NOX4/NF-kβ and TGFβ1/fibronectin/α-SMA pathways.

Abstract

Rheumatoid arthritis (RA) can cause blood pressure (BP) elevation in estrogen-deficient, post-menopausal women; however, the underlying mechanisms are not well understood. In this study, the aortic involvement and its underlying mechanisms that contribute to the BP elevation in estrogen-deficient, RA condition were identified. Ovariectomy was performed to create a state of estrogen deficiency and RA was then induced in ovariectomized rats by using incomplete Freund's adjuvant and immune-mediated collagen type-II. Ovariectomized, RA-induced rats (Ovx + RA) were given either 17β-estradiol, baricitinib, or losartan. Direct blood pressure (BP) monitoring was made via cannulation of the carotid artery. Rats were then sacrificed and the aorta was harvested followed by H&E and Picrosirius staining to evaluate histological changes and collagen deposition. Oxidative stress, inflammation, apoptosis, growth, and fibrosis levels in the aorta were assessed by using molecular biological techniques. Mean arterial pressure (MAP) was significantly elevated in Ovx + RA rats when compared to sham and Ovx rats (p < 0.05). 17β-estradiol and losartan treatment significantly reduced the MAP and heart rate in Ovx + RA rats when compared to untreated Ovx + RA rats. Expression of iNOS, Nox2 and Nox4, TLR4, NF-ĸB, TNF-α, VEGF, FGF-2, αSMA, eNOS, and caspase-3 were elevated in the aorta of Ovx + RA rats and were reduced upon 17β-estradiol treatment. However, expression of TGFβ1, Bax-2, fibronectin, and Smad2 in the aorta of Ovx + RA rats was increased following 17β-estradiol treatment (p < 0.05 compared to without treatment). The presence of RA with estrogen deficiency enhanced the BP elevation due to changes in the aorta which could be ameliorated by estrogen.