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Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness.

ABSTRACT: Hypotension in aryl hydrocarbon receptor knockout mice (ahr(-/-)) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr(-/-) (ECahr(-/-)) mice would exhibit a similar phenotype. We generated ECahr(-/-) mice by crossing AHR floxed mice (ahr(fx/fx)) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior to and following an acute injection of Ang II or chronic treatment with an angiotensin converting enzyme inhibitor (ACEi). ECahr(-/-) mice were hypotensive (ECahr(+/+): 116.1±1.4; ECahr(-/-): 107.4±2.0 mmHg, n=11, p<0.05) and exhibited significantly different responses to Ang II and ACEi. While Ang II increased BP in both genotypes, the increase was sustained in ECahr(+/+), whereas the increase in ECahr(-/-) mice steadily declined. Area under the curve analysis showed that Ang II-induced increase in diastolic BP (DBP) over 30 min was significantly lower in ECahr(-/-) mice (ECahr(+/+) 1297±223 mmHg/30 min; ECahr(-/-)(AUC): 504±138 mmHg/30 min, p<0.05). In contrast, while ACEi decreased BP in both genotypes, the subsequent rise in DBP after treatment was significantly delayed in the ECahr(-/-) mice. ECahr(-/-) mice also exhibited reduced vascular and adipose Ang II type 1 receptor (AT1R) expression, and reduced aortic Ang II-dependent vasoconstriction in the presence of vascular adipose. Taken together these data suggest that hypotension in ECahr(-/-) mice results from reduced vascular responsiveness to Ang II that is influenced by AT1R expression and adipose.

SUBMITTER: Agbor LN

PROVIDER: S-EPMC3148414 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness.

Agbor Larry N LN Elased Khalid M KM Walker Mary K MK

Biochemical pharmacology 20110613 5

Hypotension in aryl hydrocarbon receptor knockout mice (ahr(-/-)) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr(-/-) (ECahr(-/-)) mice would exhibit a similar phenotype. We generated ECahr(-/-) mice by crossing AHR floxed mice (ahr(fx/fx)) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior ...[more]

PMID: 21684261

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Project description:Previous studies have demonstrated that pre-pubertal aryl hydrocarbon receptor knockout (AHRKO) mice have slow antral follicle growth and reduced capacity to produce estradiol compared to wild-type (WT) mice. Although previous studies have suggested that this is likely due to a reduced ability of the AHRKO follicles to respond to follicle-stimulating hormone (FSH), this possibility was not directly tested. Thus, the goal of these studies was to test the hypothesis that low FSH responsiveness is responsible for the slow growth and reduced estradiol production observed in pre-pubertal AHRKO versus WT antral follicles.Antral follicles from WT and AHRKO mice were cultured with varying amounts of FSH (0-15 IU/mL) for up to 7 days, and subjected to measurements of growth, FSH receptor and steroidogenic regulator expression, sex steroid hormone levels, and inhibin beta-A expression. General linear models (GLM) for repeated measures were used to compare follicle diameters over time among treatments. If the global tests from GLM were significant, Tukey's tests were used for pairwise comparisons. Remaining comparisons among groups were performed using one-way analysis of variance followed by Tukey's post hoc test.The results indicate that FSH stimulated growth in both WT and AHRKO follicles, but that high levels of FSH (10-15 IU/mL) were required for AHRKO follicles to reach maximal growth, whereas lower levels of FSH (5 IU/mL) were required for WT follicles to reach maximal growth. Further, FSH stimulated expression of FSH receptor, steroidogenic factors, and inhibin beta-A as well as production of steroid hormones in both WT and AHRKO follicles, but the degree of stimulation differed between WT and AHRKO follicles. Interestingly, FSH treatment increased expression of FSH receptor, some steroidogenic regulators, inhibin beta-A, and steroid hormone production more in AHRKO follicles compared to WT follicles.Collectively, these data suggest that the slow growth, but not reduced steroidogenesis in AHRKO follicles, is due to their reduced ability to respond to FSH compared to WT follicles. These data also suggest that the AHR may contribute to the ability of FSH to stimulate proper follicle growth, but it may not contribute to FSH-induced steroidogenesis.

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Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness.

Publications

Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness.

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