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Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension.

ABSTRACT: Glucocorticoid-mediated hypertension is incompletely understood. Recent studies have suggested the primary mechanism of this form of hypertension may be through the effects of glucocorticoids on vascular tissues and not to excess sodium and water re-absorption as traditionally believed.The goal of this study was to better understand the role of the vasculature in the generation and maintenance of glucocorticoid-mediated hypertension.We created a mouse model with a tissue-specific knockout of the glucocorticoid receptor in the vascular endothelium.We show that these mice are relatively resistant to dexamethasone-induced hypertension. After 1 week of dexamethasone treatment, control animals have a mean blood pressure (BP) increase of 13.1 mmHg, whereas knockout animals have only a 2.7 mmHg increase (P < 0.001). Interestingly, the knockout mice have slightly elevated baseline BP compared with the controls (112.2 ± 2.5 vs. 104.6 ± 1.2 mmHg, P = 0.04), a finding which is not entirely explained by our data. Furthermore, we demonstrate that the knockout resistance arterioles have a decreased contractile response to dexamethasone with only 6.6% contraction in knockout vessels compared with 13.4% contraction in control vessels (P = 0.034). Finally, we show that in contrast to control animals, the knockout animals are able to recover a significant portion of their normal circadian BP rhythm, suggesting that the vascular endothelial glucocorticoid receptor may function as a peripheral circadian clock.Our study highlights the importance of the vascular endothelial glucocorticoid receptor in several fundamental physiologic processes, namely BP homeostasis and circadian rhythm.

SUBMITTER: Goodwin JE

PROVIDER: S-EPMC3439131 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension.

Goodwin Julie E JE Zhang Junhui J Gonzalez David D Albinsson Sebastian S Geller David S DS

Journal of hypertension 20110701 7

<h4>Background</h4>Glucocorticoid-mediated hypertension is incompletely understood. Recent studies have suggested the primary mechanism of this form of hypertension may be through the effects of glucocorticoids on vascular tissues and not to excess sodium and water re-absorption as traditionally believed.<h4>Objective</h4>The goal of this study was to better understand the role of the vasculature in the generation and maintenance of glucocorticoid-mediated hypertension.<h4>Methods</h4>We created ...[more]

PMID: 21659825

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Project description:Atorvastatin has been shown to be a safe and effective non-surgical treatment option for patients with chronic subdural hematoma. However, treatment with atorvastatin is not effective in some patients, who must undergo further surgical treatment. Dexamethasone has anti-inflammatory and immunomodulatory effects, and low dosages are safe and effective for the treatment of many diseases, such as ankylosing spondylitis and community-acquired pneumonia. However, the effects of atorvastatin and low-dose dexamethasone for the treatment of chronic subdural hematoma remain poorly understood. Hematoma samples of patients with chronic subdural hematoma admitted to the General Hospital of Tianjin Medical University of China were collected and diluted in endothelial cell medium at 1:1 as the hematoma group. Atorvastatin, dexamethasone, or their combination was added to the culture medium. The main results were as follows: hopping probe ion conductance microscopy and permeability detection revealed that the best dosages to improve endothelial cell permeability were 0.1 μM atorvastatin and 0.1 μM dexamethasone. Atorvastatin, dexamethasone, or their combination could markedly improve the recovery of injured endothelial cells. Mice subcutaneously injected with diluted hematoma solution and then treated with atorvastatin, dexamethasone, or their combination exhibited varying levels of rescue of endothelial cell function. Hopping probe ion conductance microscopy, western blot assay, and polymerase chain reaction to evaluate the status of human cerebral endothelial cell status and expression level of tight junction protein indicated that atorvastatin, dexamethasone, or their combination could reduce subcutaneous vascular leakage caused by hematoma fluid. Moreover, the curative effect of the combined treatment was significantly better than that of either single treatment. Expression of Krüppel-like factor 2 protein in human cerebral endothelial cells was significantly increased, as was expression of the tight junction protein and vascular permeability marker vascular endothelial cadherin in each treatment group compared with the hematoma stimulation group. Hematoma fluid in patients with chronic subdural hematoma may damage vascular endothelial cells. However, atorvastatin combined with low-dose dexamethasone could rescue endothelial cell dysfunction by increasing the expression of tight junction proteins after hematoma injury. The effect of combining atorvastatin with low-dose dexamethasone was better than that of atorvastatin alone. Increased expression of Krüppel-like factor 2 may play an important role in the treatment of chronic subdural hematoma. The animal protocols were approved by the Animal Care and Use Committee of Tianjin Medical University of China on July 31, 2016 (approval No. IRB2016-YX-036). The study regarding human hematoma samples was approved by the Ethics Committee of Tianjin Medical University of China on July 31, 2018 (approval No. IRB2018-088-01).

Dataset Information

Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension.

Publications

Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension.

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