title: Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats: roles of oxidative stress and perivascular adipose tissue.
abstract: Ovarian hormone loss increases reactive oxidative species, endothelial dysfunction, and cardiovascular disease. Because perivascular adipose tissue (PVAT) regulates endothelial function, we hypothesized that reactive oxidative species in PVAT mediate adverse microvascular effects of ovarian hormone deficiency. Rats were ovariectomized or sham operated and given vehicle or tempol for 6 weeks. Mesenteric resistance arterioles from ovariectomized compared with sham-operated rats had dysfunctional responses to acetylcholine (ACh) including decreased ACh-induced endothelium-dependent relaxation (50±6% versus 72±2%) and endothelium-dependent relaxation factor (17±4% versus 37±2%) and increased endothelium-dependent contracting factor (27±5% versus 9±3%). OVX rat mesenteric arterioles had increased contractions to the thromboxane/prostanoid receptor agonist U-46 619 (58±3% versus 40±5%) and increased reactive oxidative species (tempo-9-AC fluorescence) with U-46 619 (0.65±0.17 versus 0.14±0.06 Δ unit) or ACh (0.49±0.09 versus 0.09±0.05 Δ unit) and increased p22(phox) protein expression (0.89±0.05 versus 0.18±0.04 Δ unit), whereas nitric oxide activity (DAF-FM [4-amino-5-methylamino-2',7'-difluorofluorescein diacetate] fluorescence) with ACh was reduced (0.39±0.1 versus 0.70±0.10 Δ unit). No differences were found in endothelium-dependent hyperpolarizing factor or contractile responses to phenylephrine. PVAT enhanced ACh-induced relaxation, endothelium-dependent relaxation factor, and nitric oxide only in sham-operated rats. Tempol prevented ovariectomy-induced endothelial dysfunction and restored the enhancing effects of PVAT on ACh-induced relaxation, endothelium-dependent relaxation factor, and nitric oxide in ovariectomized rat vessels, but both tempol and PVAT were required to normalize the enhanced U-46 619 contractions after ovariectomy. In conclusion, ovariectomy redirects endothelial responses from relaxation to contraction by reducing vascular nitric oxide, augmenting thromboxane/prostanoid receptor signaling, and attenuating the vasodilatory effects of PVAT, all of which were dependent on reactive oxidative species.
authors.affiliation: Division of Nephrology and Hypertension, Georgetown University Medical Center, 6 PHC, Suite F6003, 3800 Reservoir Rd NW, Washington, DC 20007. wilcoxch@georgetown.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Xie
authors.initials: X
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sandberg
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology*; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D010656:Phenylephrine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; C001803:tempol
keywords: menopause; nitric oxide; ovariectomy; reactive oxygen species; tempol; thromboxane prostanoid receptors