期刊
HYPERTENSION
卷 63, 期 5, 页码 1063-1069出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.113.02284
关键词
menopause; nitric oxide; ovariectomy; reactive oxygen species; tempol; thromboxane prostanoid receptors
资金
- National Kidney Foundation Capital Area
- Marriott Cardiovascular Research Fellowship from National Institutes of Health [AG/HL-19291, AG-039779, AG-16902]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-049870, DK-036079]
- National Heart, Lung, and Blood Institute [HL-68686]
- George E. Schreiner Chair of Nephrology
- Hypertension, Kidney and Vascular Research Center
- Chinese Government Scholarship Program
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 unit) or ACh (0.49 +/- 0.09 versus 0.09 +/- 0.05 unit) and increased p22(phox) protein expression (0.89 +/- 0.05 versus 0.18 +/- 0.04 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 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.
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