Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension
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 inhib...
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| Format: | Article |
| Language: | English |
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Wiley
2021-07-01
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| Series: | Pulmonary Circulation |
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| Online Access: | https://doi.org/10.1177/20458940211025240 |
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| author | Divya P. Menon Guanming Qi Seung K. Kim M. Elizabeth Moss Krishna C. Penumatsa Rod R. Warburton Deniz Toksoz Jamie Wilson Nicholas S. Hill Iris Z. Jaffe Ioana R. Preston |
| author_facet | Divya P. Menon Guanming Qi Seung K. Kim M. Elizabeth Moss Krishna C. Penumatsa Rod R. Warburton Deniz Toksoz Jamie Wilson Nicholas S. Hill Iris Z. Jaffe Ioana R. Preston |
| author_sort | Divya P. Menon |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-3bd289a1759d4c7eab24592dde2d3cab |
| institution | OA Journals |
| issn | 2045-8940 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj-art-3bd289a1759d4c7eab24592dde2d3cab2025-08-20T02:14:16ZengWileyPulmonary Circulation2045-89402021-07-0111311310.1177/20458940211025240Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertensionDivya P. Menon0Guanming Qi1Seung K. Kim2M. Elizabeth Moss3Krishna C. Penumatsa4Rod R. Warburton5Deniz Toksoz6Jamie Wilson7Nicholas S. Hill8Iris Z. Jaffe9Ioana R. Preston10Pulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAMolecular Cardiology Research InstituteTufts Medical CenterBostonMAUSAMolecular Cardiology Research InstituteTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAMolecular Cardiology Research InstituteTufts Medical CenterBostonMAUSAPulmonary, Critical Care and Sleep DivisionTufts Medical CenterBostonMAUSAAbnormalities 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.https://doi.org/10.1177/20458940211025240pulmonary hypertensionexperimentalright ventriclespironolactonemineralocorticoid receptorendothelial cell |
| spellingShingle | Divya P. Menon Guanming Qi Seung K. Kim M. Elizabeth Moss Krishna C. Penumatsa Rod R. Warburton Deniz Toksoz Jamie Wilson Nicholas S. Hill Iris Z. Jaffe Ioana R. Preston Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension Pulmonary Circulation pulmonary hypertension experimental right ventricle spironolactone mineralocorticoid receptor endothelial cell |
| title | Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension |
| title_full | Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension |
| title_fullStr | Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension |
| title_full_unstemmed | Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension |
| title_short | Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension |
| title_sort | vascular cell specific roles of mineralocorticoid receptors in pulmonary hypertension |
| topic | pulmonary hypertension experimental right ventricle spironolactone mineralocorticoid receptor endothelial cell |
| url | https://doi.org/10.1177/20458940211025240 |
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