title: The effects of pravastatin on the normal human placenta: Lessons from ex-vivo models.
abstract: BACKGROUND
  Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus.
  
  
  METHODS
  In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II.
  
  
  RESULTS
  The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. eNOS expression was significantly increased in PraM cotyledons but not in pravastatin-treated placental explants cultured under normoxia or hypoxia. eNOS phosphorylation was not significantly affected by pravastatin. The feto-placental vascular tone and the fetal vasoconstriction response to angiotensin-II, did not change following exposure of the maternal circulation to pravastatin.
  
  
  CONCLUSIONS
  We found that pravastatin does not alter the essential physiological functions of the placenta investigated in the study. The relevance of the study lays in the fact that it expands the current knowledge obtained thus far regarding the effect of the drug on the normal human placenta. This data is reassuring and important for clinicians that consider the treatment of high-risk patients with pravastatin, a treatment that exposes some normal pregnancies to the drug.
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Adelina
authors.initials: A
authors.lastname: Balan
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Szaingurten-Solodkin
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Shani S
authors.initials: SS
authors.lastname: Swissa
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Valeria
authors.initials: V
authors.lastname: Feinshtein
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Huleihel
authors.affiliation: Department of Obstetrics and Gynecology, Soroka University Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Gershon
authors.initials: G
authors.lastname: Holcberg
authors.affiliation: Department of Obstetrics and Gynecology, Soroka University Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Dukler
authors.affiliation: Department of Obstetrics and Gynecology, Soroka University Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ofer
authors.identifier: http://orcid.org/0000-0001-5317-4512
authors.initials: O
authors.lastname: Beharier
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000071063:Endoglin / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D000072483:Placenta Growth Factor / Q000235:genetics / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D011247:Pregnancy; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; C064206:ENG protein, human; D000071063:Endoglin; D000072483:Placenta Growth Factor; D052250:Nitric Oxide Synthase Type III; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin