Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism
<h3>Objectives</h3><p dir="ltr">A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weig...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , |
| منشور في: |
2020
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| الموضوعات: | |
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| _version_ | 1864513558895656960 |
|---|---|
| author | Eleftheria Lefkou (17052414) |
| author2 | Katerina Varoudi (17093032) Joaquim Pombo (540952) Aleksandar Jurisic (17052408) Zaklina Jurisic (17052411) Greg Contento (8267055) Guillermina Girardi (340464) |
| author2_role | author author author author author author |
| author_facet | Eleftheria Lefkou (17052414) Katerina Varoudi (17093032) Joaquim Pombo (540952) Aleksandar Jurisic (17052408) Zaklina Jurisic (17052411) Greg Contento (8267055) Guillermina Girardi (340464) |
| author_role | author |
| dc.creator.none.fl_str_mv | Eleftheria Lefkou (17052414) Katerina Varoudi (17093032) Joaquim Pombo (540952) Aleksandar Jurisic (17052408) Zaklina Jurisic (17052411) Greg Contento (8267055) Guillermina Girardi (340464) |
| dc.date.none.fl_str_mv | 2020-12-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.bcp.2020.114217 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Triple_therapy_with_pravastatin_low_molecular_weight_heparin_and_low_dose_aspirin_improves_placental_haemodynamics_and_pregnancy_outcomes_in_obstetric_antiphospholipid_syndrome_in_mice_and_women_through_a_nitric_oxide-dependent_mechanism/24242611 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Pharmacology and pharmaceutical sciences Reproductive medicine Antiphospholipid syndrome Pregnancy Placental insufficiency Preeclampsia Intrauterine growth restriction Uterine arteries Dopplers Low molecular weight heparin Low dose aspirin Pravastatin Wire myography Mouse model Nitric oxide synthetase Nitric oxide |
| dc.title.none.fl_str_mv | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Objectives</h3><p dir="ltr">A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis.</p><p><br></p><h3>Methods</h3><p dir="ltr">Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS.</p><h3>Results</h3><p dir="ltr">The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies.</p><h3>Conclusion</h3><p dir="ltr">LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial.</p><h2>Other Information</h2><p dir="ltr">Published in: Biochemical Pharmacology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.bcp.2020.114217" target="_blank">https://dx.doi.org/10.1016/j.bcp.2020.114217</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_1452edafde50de0dd4e8040c3c947384 |
| identifier_str_mv | 10.1016/j.bcp.2020.114217 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/24242611 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanismEleftheria Lefkou (17052414)Katerina Varoudi (17093032)Joaquim Pombo (540952)Aleksandar Jurisic (17052408)Zaklina Jurisic (17052411)Greg Contento (8267055)Guillermina Girardi (340464)Biomedical and clinical sciencesPharmacology and pharmaceutical sciencesReproductive medicineAntiphospholipid syndromePregnancyPlacental insufficiencyPreeclampsiaIntrauterine growth restrictionUterine arteries DopplersLow molecular weight heparinLow dose aspirinPravastatinWire myographyMouse modelNitric oxide synthetaseNitric oxide<h3>Objectives</h3><p dir="ltr">A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis.</p><p><br></p><h3>Methods</h3><p dir="ltr">Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS.</p><h3>Results</h3><p dir="ltr">The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies.</p><h3>Conclusion</h3><p dir="ltr">LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial.</p><h2>Other Information</h2><p dir="ltr">Published in: Biochemical Pharmacology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.bcp.2020.114217" target="_blank">https://dx.doi.org/10.1016/j.bcp.2020.114217</a></p>2020-12-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.bcp.2020.114217https://figshare.com/articles/journal_contribution/Triple_therapy_with_pravastatin_low_molecular_weight_heparin_and_low_dose_aspirin_improves_placental_haemodynamics_and_pregnancy_outcomes_in_obstetric_antiphospholipid_syndrome_in_mice_and_women_through_a_nitric_oxide-dependent_mechanism/24242611CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/242426112020-12-01T00:00:00Z |
| spellingShingle | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism Eleftheria Lefkou (17052414) Biomedical and clinical sciences Pharmacology and pharmaceutical sciences Reproductive medicine Antiphospholipid syndrome Pregnancy Placental insufficiency Preeclampsia Intrauterine growth restriction Uterine arteries Dopplers Low molecular weight heparin Low dose aspirin Pravastatin Wire myography Mouse model Nitric oxide synthetase Nitric oxide |
| status_str | publishedVersion |
| title | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| title_full | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| title_fullStr | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| title_full_unstemmed | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| title_short | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| title_sort | Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism |
| topic | Biomedical and clinical sciences Pharmacology and pharmaceutical sciences Reproductive medicine Antiphospholipid syndrome Pregnancy Placental insufficiency Preeclampsia Intrauterine growth restriction Uterine arteries Dopplers Low molecular weight heparin Low dose aspirin Pravastatin Wire myography Mouse model Nitric oxide synthetase Nitric oxide |