The transfer of pravastatin in the dually perfused human placenta

Zarek, Judith; DeGorter, Marianne K.; Lubetsky, Angelika; Kim, R.B.; Laskin, Carl A.; Berger, Howard; Koren, Gideon

doi:10.1016/j.placenta.2013.05.002

Cited by 35 publications

(27 citation statements)

References 13 publications

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“…Indeed, in human first trimester placental explants, pravastatin inhibits insulin-like growth factor 1 receptor function with adverse implications for trophoblast differentiation (39). With regard to the fetus, the levels of pravastatin achieved within the fetal circulation in this current study are unknown, but earlier studies have demonstrated that transfer of pravastatin in ex vivo human placenta occurs albeit to a limited extent (40,41). However, it is of interest to note that we observed no induction of Vegfa expression in Hsd11b2 −/− fetal heart, suggesting that if pravastatin is eliciting direct effects on the fetus, it may be via different pathways.…”

Section: Discussionmentioning

confidence: 79%

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Wyrwoll

Noble

Thomson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role. We previously discovered that Hsd11b2 −/− mice, lacking 11β-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2 +/+ , Hsd11b2 +/− , and Hsd11b2 −/− littermates from heterozygous (Hsd11b +/− ) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2 −/− fetuses did not undergo the normal gestational increase seen in Hsd11b2 +/+ littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11β-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2 −/− fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2 −/− fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2 −/− fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.placenta | 11β-HSD2 | glucocorticoids | fetal heart | developmental programming

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Section: Discussionmentioning

confidence: 79%

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Wyrwoll

Noble

Thomson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Maternal lesions of underperfusion are thought to mediate utero-placental ischemia, which has been proposed as a mechanism of disease in preeclampsia [55,62–73], intrauterine growth restriction [55,62–64,66–68,71,74–79], fetal death [64,66,68,80,81] and abruptio placenta (ischemic placental disease) [52–57,64,66,68,82,83], preterm labor [64,66,68,84–90], preterm prelabor rupture of membranes [64,66,68,91,92], recurrent spontaneous abortion [17,93] and massive perivillous fibrin deposition [94–108]. It is important to clarify that the nosology of maternal vascular lesions consistent with underperfusion includes acute atherosis, and that we examined its association with other villous and vascular lesions consistent with maternal vascular underperfusion.…”

Section: Discussionmentioning

confidence: 99%

Placental lesions associated with acute atherosis

Kim

Chaemsaithong

Romero

et al. 2014

The Journal of Maternal-Fetal & Neonatal Medicine

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Objective Acute atherosis is a lesion of the spiral arteries characterized by fibrinoid necrosis of the vessel wall, an accumulation of fat-containing macrophages, and a mononuclear perivascular infiltrate, which can be found in patients with preeclampsia, fetal death, small-for-gestational age (SGA), spontaneous preterm labor/premature prelabor rupture of membrane, and spontaneous mid-trimester abortion. This lesion is thought to decrease blood flow to the intervillous space which may lead to other vascular lesions of the placenta. The objective of this study was to test whether there is an association between acute atherosis and placental lesions that are consistent with maternal vascular underperfusion, amniotic fluid infection, fetal vascular thrombo-occlusive disease or chronic inflammation. Material and methods A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women’s Hospital/Detroit Medical Center was conducted examine 16,457 placentas. The frequency of placenta lesions (diagnosed using the criteria of the Perinatal Section of the Society for Pediatric Pathology) was compared between pregnancies with and without atherosis. Results Among 16,457 women who were enrolled, 10.2% (1,671/16,457) were excluded, leaving 14,786 women who contributed data for analysis. Among them, the prevalence of acute atherosis was 2.2% (326/14,786). Women with acute atherosis were more than six times as likely as those without to have placental lesions consistent with maternal underperfusion (adjusted odds ratio- aOR: 6.7; 95% CI 5.2–8.6). To a lesser degree, acute atherosis was also associated with greater risks of having either lesions consistent with fetal vascular thrombo-occlusive disease (aOR 1.7; 95% CI 1.2–2.3) or chronic chorioamnionitis (aOR 1.9; 95% CI 1.3–3), but not with other chronic inflammatory lesions, after adjusting for gestational age at delivery. In contrast, women with acute atherosis were 60% less likely to have lesions consistent with amniotic fluid infecition, adjusting for gestational age at delivery (aOR 0.4; 95% CI 0.3–0.5). Conclusions Acute atherosis is associated with increased risks of having placental lesions consistent with maternal vascular underperfusion, and to a lesser extent, chronic chorioamnionitis and those consistent with fetal vascular thrombo-occlusive disease.

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“…This is also indirectly supported by studies attempting fetal gene therapy using various adenoviruses in which only intra-amniotic or direct fetal administration of the virus vector is used to achieve adequate fetal expression [40]–[43]. Similarly, pravastatin is a hydrophilic statin and subject to efflux transporters at the placenta and blood brain barrier [44]–[48]. We therefore believe that the ability of pravastatin to achieve the changes seen in offspring born to preeclamptic dams are not due to direct effects of pravastatin on the offspring but rather through amelioration of the intrauterine environment.…”

Section: Discussionmentioning

confidence: 99%

Maternal Pravastatin Prevents Altered Fetal Brain Development in a Preeclamptic CD-1 Mouse Model

et al. 2014

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ObjectiveUsing an animal model, we have previously shown that preeclampsia results in long-term adverse neuromotor outcomes in the offspring, and this phenotype was prevented by antenatal treatment with pravastatin. This study aims to localize the altered neuromotor programming in this animal model and to evaluate the role of pravastatin in its prevention.Materials and MethodsFor the preeclampsia model, pregnant CD-1 mice were randomly allocated to injection of adenovirus carrying sFlt-1 or its control virus carrying mFc into the tail vein. Thereafter they received pravastatin (sFlt-1-pra “experimental group”) or water (sFlt-1 “positive control”) until weaning. The mFc group (“negative control”) received water. Offspring at 6 months of age were sacrificed, and whole brains underwent magnetic resonance imaging (MRI). MRIs were performed using an 11.7 Tesla vertical bore MRI scanner. T2 weighted images were acquired to evaluate the volumes of 28 regions of interest, including areas involved in adaptation and motor, spatial and sensory function. Cytochemistry and cell quantification was performed using neuron-specific Nissl stain. One-way ANOVA with multiple comparison testing was used for statistical analysis.ResultsCompared with control offspring, male sFlt-1 offspring have decreased volumes in the fimbria, periaquaductal gray, stria medullaris, and ventricles and increased volumes in the lateral globus pallidus and neocortex; however, female sFlt-1 offspring showed increased volumes in the ventricles, stria medullaris, and fasciculus retroflexus and decreased volumes in the inferior colliculus, thalamus, and lateral globus pallidus. Neuronal quantification via Nissl staining exhibited decreased cell counts in sFlt-1 offspring neocortex, more pronounced in males. Prenatal pravastatin treatment prevented these changes.ConclusionPreeclampsia alters brain development in sex-specific patterns, and prenatal pravastatin therapy prevents altered neuroanatomic programming in this animal model.

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The transfer of pravastatin in the dually perfused human placenta

Cited by 35 publications

References 13 publications

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Placental lesions associated with acute atherosis

Maternal Pravastatin Prevents Altered Fetal Brain Development in a Preeclamptic CD-1 Mouse Model

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