Abstract
BackgroundEstrogen deficiency increases the cardiovascular risks in postmenopausal women. Inhibition of the renin-angiotensin system (RAS) and associated oxidative stress confers a cardiovascular protection, but the role of RAS in estrogen deficiency-related vascular dysfunction is unclear. The present study investigates whether the up-regulation of RAS and associated oxidative stress contributes to the development of endothelial dysfunction during estrogen deficiency in ovariectomized (OVX) rats.Methodology/Principal FindingsAdult female rats were ovariectomized with and without chronic treatment with valsartan and enalapril. Isometric force measurement was performed in isolated aortae. The expression of RAS components was determined by immunohistochemistry and Western blotting method while ROS accumulation in the vascular wall was evaluated by dihydroethidium fluorescence. Ovariectomy increased the expression of angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), NAD(P)H oxidase, and nitrotyrosine in the rat aorta. An over-production of angiotensin II and ROS was accompanied by decreased phosphorylation of eNOS at Ser1177 in OVX rat aortae. These pathophysiological changes were closely coupled with increased oxidative stress and decreased nitric oxide bioavailability, culminating in markedly impaired endothelium-dependent relaxations. Furthermore, endothelial dysfunction and increased oxidative stress in aortae of OVX rats were inhibited or reversed by chronic RAS inhibition with enalapril or valsartan.Conclusions/SignificanceThe novel findings highlight a significant therapeutic benefit of RAS blockade in the treatment of endothelial dysfunction-related vascular complications in postmenopausal states.
Highlights
Menopause is a risk factor for cardiovascular diseases as estrogen deficiency is known to impair cardiovascular function and metabolism [1]
The present study reveals a principal role of the reninangiotensin system (RAS) activation and resulting oxidative stress in the induction of endothelial dysfunction in estrogen-deficient OVX rats
Ovariectomy leads to reduced nitric oxide (NO) bioavailability which accounts for the impaired endothelium-dependent relaxations during estrogen deficiency through a cluster of inter-connected cellular events in the vascular wall: (i) increased expression of angiotensin-converting enzyme (ACE), (ii) augmented production of angiotensin II leading to overexpression of angiotensin type 1 receptor (AT1R), (iii) greater production of reactive oxygen species (ROS) due to increased expression and activity of NAD(P)H oxidase, and (iv) the increased content of nitrotyrosine, a footprint for increased formation of peroxynitrite from NO and O22
Summary
Menopause is a risk factor for cardiovascular diseases as estrogen deficiency is known to impair cardiovascular function and metabolism [1]. Loss of estrogen-dependent cardiovascular protection diminishes endothelial function, and may involve activation of the renin-angiotensin system (RAS). Clinical and animal studies indicate an inverse association between estrogen and the RAS activation [2,3,4,5,6]. Endothelial dysfunction caused by reduced bioavailability of nitric oxide (NO) and/or elevated formation of reactive oxygen species (ROS) in the vascular wall, sets into motion in a sequence of events leading to the development of cardiovascular complications [7,8]. Estrogen deficiency increases the cardiovascular risks in postmenopausal women. Inhibition of the reninangiotensin system (RAS) and associated oxidative stress confers a cardiovascular protection, but the role of RAS in estrogen deficiency-related vascular dysfunction is unclear. The present study investigates whether the up-regulation of RAS and associated oxidative stress contributes to the development of endothelial dysfunction during estrogen deficiency in ovariectomized (OVX) rats
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