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AuthorLefkou, Eleftheria
AuthorVaroudi, Katerina
AuthorPombo, Joaquim
AuthorJurisic, Aleksandar
AuthorJurisic, Zaklina
AuthorContento, Greg
AuthorGirardi, Guillermina
Available date2023-05-10T03:48:45Z
Publication Date2020-12-01
Publication NameBiochemical Pharmacology
Identifierhttp://dx.doi.org/10.1016/j.bcp.2020.114217
ISSN00062952
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85091380421&origin=inward
URIhttp://hdl.handle.net/10576/42518
AbstractObjectives: 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. Methods: 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. Results: 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. Conclusion: 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.
SponsorThe publication of this article was funded by the Qatar National Library. All the authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Languageen
PublisherElsevier
SubjectAntiphospholipid syndrome
Intrauterine growth restriction
Low dose aspirin
Low molecular weight heparin
Mouse model
Nitric oxide
Nitric oxide synthetase
Placental insufficiency
Pravastatin
Preeclampsia
Pregnancy
Uterine arteries Dopplers
Wire myography
TitleTriple 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
TypeArticle
Volume Number182
dc.accessType Open Access


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