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Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice
Jeffrey B. Hodgin, … , Oliver Smithies, Nobuyo Maeda
Jeffrey B. Hodgin, … , Oliver Smithies, Nobuyo Maeda
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):541-548. https://doi.org/10.1172/JCI14066.
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Article

Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice

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Abstract

The vasculoprotective effects of sex hormones, particularly estrogens, have been attributed to their ability to increase the bioavailability of nitric oxide through activation of endothelial nitric oxide synthase (eNOS). To dissect the relative contribution in vivo of eNOS, sex hormones, and their interaction in two complex vascular phenotypes, hypertension and atherosclerosis, we used mice doubly deficient in eNOS and apoE (nnee) or lacking only apoE (NNee). Females and males were gonadectomized at 1 month of age and implanted either with control pellets or pellets releasing 17β-estradiol (E2). Hormonally intact nnee mice have elevated blood pressure (BP) and increased atherosclerosis compared with NNee mice, but on removal of gonads, BP and atherosclerosis decreased significantly in nnee mice but not in NNee mice. Three months of treatment with exogenous E2 dramatically reduced atherosclerosis and significantly lowered BP in both NNee and nnee mice compared with animals treated with control pellets. Thus exogenous E2 has strong BP-lowering and atheroprotective effects in apoE-deficient mice, but eNOS is not essential for either effect. Endogenous sex hormones, on the other hand, cause significant damage to the vasculature in the absence of eNOS, but these effects are overridden by interactions between eNOS and sex hormones.

Authors

Jeffrey B. Hodgin, Joshua W. Knowles, Hyung-Suk Kim, Oliver Smithies, Nobuyo Maeda

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Figure 1

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BP and atherosclerotic lesion size in NNee and nnee mice, either gonadec...
BP and atherosclerotic lesion size in NNee and nnee mice, either gonadectomized and implanted with a control pellet (Gdx) or surgically intact (I). I1, current data; I2, cumulative data. The lower number in each bar is sample size (n). The upper number in each bar is mean BP (mmHg) or lesion size (×103 μm2), with SEM represented as a vertical line. (a) The BP measurements for male mice (10 Gdx NNee and 14 Gdx nnee; 35 I2NNee and 19 I2nnee) and female mice (12 Gdx NNee and 15 Gdx nnee; 22 I2NNee and 18 I2nnee; see Results for number of I1 male and female mice) were combined as described in Methods. Removal of endogenous sex hormones by gonadectomy results in a significant reduction in BP in nnee mice (*P < 0.05 versus I2, Student’s t test with Bonferroni correction for multiple comparisons). (b) Removal of endogenous sex hormones by gonadectomy results in a significant decrease in atherosclerotic lesion size in nnee mice (*P < 0.05 versus I2, Student t test with Bonferroni correction for multiple comparisons).

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