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Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

ABSTRACT: OBJECTIVE:MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNF? (tumor necrosis factor ?)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNF?-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs. CONCLUSIONS:In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective.

SUBMITTER: Moss ME

PROVIDER: S-EPMC6656626 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

Moss M Elizabeth ME Lu Qing Q Iyer Surabhi L SL Engelbertsen Daniel D Marzolla Vincenzo V Caprio Massimiliano M Lichtman Andrew H AH Jaffe Iris Z IZ

Arteriosclerosis, thrombosis, and vascular biology 20190711 8

<h4>Objective</h4>MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Furthe ...[more]

PMID: 31294624

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Project description:Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.

Dataset Information

Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

Publications

Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner.

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