Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity
Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (<i>Vdr<sup>−</sup&...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/12350 |
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| author | Miguel A. Olivencia Marta Villegas-Esguevillas Maria Sancho Bianca Barreira Elena Paternoster Rui Adão María Jesús Larriba Angel Cogolludo Francisco Perez-Vizcaino |
| author_facet | Miguel A. Olivencia Marta Villegas-Esguevillas Maria Sancho Bianca Barreira Elena Paternoster Rui Adão María Jesús Larriba Angel Cogolludo Francisco Perez-Vizcaino |
| author_sort | Miguel A. Olivencia |
| collection | DOAJ |
| description | Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (<i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup>). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. <i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup> mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, <i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup> mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of <i>Vdr</i> in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr<sup>−/−</sup> mice, resembling animals and humans suffering from PAH. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:25:12Z |
| publishDate | 2023-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-30ad7765f2194afb80a4855e1171af5a2023-11-18T23:03:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124151235010.3390/ijms241512350Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel ActivityMiguel A. Olivencia0Marta Villegas-Esguevillas1Maria Sancho2Bianca Barreira3Elena Paternoster4Rui Adão5María Jesús Larriba6Angel Cogolludo7Francisco Perez-Vizcaino8Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainCiber Enfermedades Respiratorias (CIBERES), 28029 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, SpainRecent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (<i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup>). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. <i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup> mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, <i>Vdr<sup>−</sup></i><sup>/<i>−</i></sup> mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of <i>Vdr</i> in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr<sup>−/−</sup> mice, resembling animals and humans suffering from PAH.https://www.mdpi.com/1422-0067/24/15/12350vitamin D receptorpulmonary hypertensionKv7 channelsKCNE |
| spellingShingle | Miguel A. Olivencia Marta Villegas-Esguevillas Maria Sancho Bianca Barreira Elena Paternoster Rui Adão María Jesús Larriba Angel Cogolludo Francisco Perez-Vizcaino Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity International Journal of Molecular Sciences vitamin D receptor pulmonary hypertension Kv7 channels KCNE |
| title | Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity |
| title_full | Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity |
| title_fullStr | Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity |
| title_full_unstemmed | Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity |
| title_short | Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity |
| title_sort | vitamin d receptor deficiency upregulates pulmonary artery kv7 channel activity |
| topic | vitamin D receptor pulmonary hypertension Kv7 channels KCNE |
| url | https://www.mdpi.com/1422-0067/24/15/12350 |
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