Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension
<p><strong>Background:</strong> Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effect of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5- MTHF) on the prevention and treatment of hypertensive disorders of pregnancy...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Heart Association
2024
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| _version_ | 1811140931077799936 |
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| author | Dickinson, Y Boehni, R Obeid, R Lewandowski, A Douglas, G Leeson, P Channon, K Chuaiphichai, S |
| author_facet | Dickinson, Y Boehni, R Obeid, R Lewandowski, A Douglas, G Leeson, P Channon, K Chuaiphichai, S |
| author_sort | Dickinson, Y |
| collection | OXFORD |
| description | <p><strong>Background:</strong> Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effect of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5- MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remains unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy, and possible consequences for endothelial nitric oxide (NO) generation, maternal blood pressure (BP) and fetal growth.</p>
<p><strong>Methods:</strong> We analysed the maternal BP in pregnant wild-type (Gch1fl/fl) and Gch1fl/flTie2cre mice treated with either FA or 5-MTHF starting at before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by HPLC.</p>
<p><strong>Results:</strong> In vitro studies in mouse and human endothelial cells showed that treatment with 5- MTHF, but not FA, elevated BH4 levels, reduced superoxide production and increased NO synthase (NOS) activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NOS activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented, and treated, hypertension in pregnancy, when administered either prior to or during pregnancy, respectively, and normalised placental and fetal growth restriction if administered from mid-gestation onwards.</p>
<p><strong>Conclusion:</strong> Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NOS activity. Thus, 5- MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.</p> |
| first_indexed | 2024-09-25T04:29:49Z |
| format | Journal article |
| id | oxford-uuid:657897f8-429d-4445-ab72-09c5d395f30a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:29:49Z |
| publishDate | 2024 |
| publisher | American Heart Association |
| record_format | dspace |
| spelling | oxford-uuid:657897f8-429d-4445-ab72-09c5d395f30a2024-08-27T08:56:29ZNovel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertensionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:657897f8-429d-4445-ab72-09c5d395f30aEnglishSymplectic ElementsAmerican Heart Association2024Dickinson, YBoehni, RObeid, RLewandowski, ADouglas, GLeeson, PChannon, KChuaiphichai, S<p><strong>Background:</strong> Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effect of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5- MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remains unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy, and possible consequences for endothelial nitric oxide (NO) generation, maternal blood pressure (BP) and fetal growth.</p> <p><strong>Methods:</strong> We analysed the maternal BP in pregnant wild-type (Gch1fl/fl) and Gch1fl/flTie2cre mice treated with either FA or 5-MTHF starting at before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by HPLC.</p> <p><strong>Results:</strong> In vitro studies in mouse and human endothelial cells showed that treatment with 5- MTHF, but not FA, elevated BH4 levels, reduced superoxide production and increased NO synthase (NOS) activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NOS activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented, and treated, hypertension in pregnancy, when administered either prior to or during pregnancy, respectively, and normalised placental and fetal growth restriction if administered from mid-gestation onwards.</p> <p><strong>Conclusion:</strong> Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NOS activity. Thus, 5- MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.</p> |
| spellingShingle | Dickinson, Y Boehni, R Obeid, R Lewandowski, A Douglas, G Leeson, P Channon, K Chuaiphichai, S Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title | Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title_full | Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title_fullStr | Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title_full_unstemmed | Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title_short | Novel role of 5-methyl-(6S)-tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
| title_sort | novel role of 5 methyl 6s tetrahydrofolate in mediating endothelial cell tetrahydrobiopterin in pregnancy and implications for gestational hypertension |
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