Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.

• MeSH
• akridiny farmakologie   MeSH
• buňky MDCK MeSH
• látky proti HIV krev   metabolismus   farmakologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• maravirok krev   metabolismus   MeSH
• nádorové buněčné linie MeSH
• P-glykoproteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• perfuze MeSH
• placenta účinky léků   metabolismus   MeSH
• placentární oběh MeSH
• přenašeče organických aniontů antagonisté a inhibitory   genetika   metabolismus   MeSH
• protein OATP1B3 antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• psi MeSH
• regulace genové exprese MeSH
• ritonavir farmakologie   MeSH
• těhotenství MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several autoimmune, cancer, and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ATP-binding cassette (ABC) efflux transporters that have a recognized role in the protection of a developing fetus: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance protein 2 (ABCC2). We found that maraviroc does not inhibit any of the three studied ABC transporters and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine P-glycoprotein (Abcb1) expressed in Madin-Darby canine kidney II (MDCKII) cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the fetal-to-maternal direction, which suggests that ABCB1/Abcb1 facilitates in situ maraviroc transport. This transplacental transport was saturable and significantly diminished after the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood. SIGNIFICANCE STATEMENT: Antiretroviral drug maraviroc shows low toxicity and is thus a good candidate for prevention of mother-to-child transmission of human immunodeficiency virus when failure of recommended therapy occurs. Using in vitro cell-based experiments and in situ dually perfused rat term placenta, we examined maraviroc interaction with the placental ABC drug transporters ABCB1, ABCG2, and ABCC2. We demonstrate for the first time that placental ABCB1 significantly reduces mother-to-fetus transport of maraviroc, which suggests that ABCB1 may be responsible for the low cord-blood/maternal-blood ratio observed in humans.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• antagonisté receptoru CCR5 farmakokinetika   terapeutické užití   MeSH
• buňky MDCK MeSH
• HIV infekce farmakoterapie   MeSH
• infekční komplikace v těhotenství farmakoterapie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• maravirok farmakokinetika   terapeutické užití   MeSH
• maternofetální výměna látek * MeSH
• modely u zvířat MeSH
• P-glykoprotein metabolismus   MeSH
• permeabilita MeSH
• placenta metabolismus   MeSH
• placentární oběh MeSH
• plod metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• psi MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alcohol abuse during pregnancy is a well-known factor in fetal morbidity, including smaller fetal size. We have shown that chronic hypoxia, considered the main pathogenetic factor in intrauterine growth restriction, elevates fetoplacental vascular resistance (and vasoconstrictor reactivity) and thus, presumably, reduces placental blood flow. We thus hypothesized that alcohol may affect the fetus - in addition to other mechanisms - by altering fetoplacental vascular resistance and/or reactivity. Using isolated, double-perfused rat placenta model, we found that maternal alcohol intake in the last third of gestation doubled the vasoconstrictor responses to angiotensin II but did not affect resting vascular resistance. Reactivity to acute hypoxic challenges was unchanged. Chronic maternal alcohol intake in a rat model alters fetoplacental vasculature reactivity; nevertheless, these changes do not appear as serious as other detrimental effects of alcohol on the fetus.

• MeSH
• placentární oběh * MeSH
• potkani Wistar MeSH
• spektrum vrozených alkoholových poruch etiologie   MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• vazokonstrikce * MeSH
• zvířata MeSH
• Check Tag
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Endocrine disruptors (EDs) are known to have harmful effects on the human endocrine system; special effort is actually given to the exposure during pregnancy. Humans are usually exposed to a mixture of EDs, which may potentiate or antagonize each other, and the combined effect may be difficult to estimate. The main phthalate monoesters monoethyl-, mono-n-butyl-, monoisobutyl-, monobenzyl-, mono-(2-ethylhexyl)-, mono-(2-ethyl-5-hydroxyhexyl)- and mono-(2-ethyl-5-oxohexyl) phthalate were determined in 18 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography-tandem mass spectrometry. Previously determined levels of selected bisphenols, parabens and steroids were also considered in this study. In cord blood, there were significantly higher mono-n-butyl phthalate levels than in maternal blood (p=0.043). The results of multiple regression models showed that maternal plasma phthalates were negatively associated with cord plasma androstenedione, testosterone and dehydroepiandrosterone and positively associated with estradiol and estriol. For estriol, a cumulative association was also observed for sumabisphenols. To the best of our knowledge, this is the first pilot study evaluating the effect of prenatal exposure by multiple EDs on newborn steroidogenesis. Our results confirmed phthalate accumulation in the fetal area and disruption of fetal steroidogenesis. This preliminary study highlights the negative impacts of in utero EDs exposure on fetal steroidogenesis.

• MeSH
• dospělí MeSH
• endokrinní disruptory škodlivé účinky   krev   farmakologie   MeSH
• fetální krev účinky léků   metabolismus   MeSH
• kyseliny ftalové škodlivé účinky   krev   farmakologie   MeSH
• lidé MeSH
• matka - expozice noxám * škodlivé účinky   MeSH
• pilotní projekty MeSH
• placentární oběh účinky léků   fyziologie   MeSH
• steroidy antagonisté a inhibitory   krev   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Intrahepatic cholestasis of pregnancy (ICP) is a frequent liver disorder, mostly occurring in the third trimester. ICP is not harmful to the mothers but threatens the fetus. The authors evaluated steroid alterations in maternal and mixed umbilical blood to elucidate their role in the ICP development. Ten women with ICP were included in the study. Steroids in the maternal blood were measured by Gas Chromatography-Mass Spectrometry (GC-MS) (n=58) and RIA (n=5) at the diagnosis of ICP, labor, day 5 postpartum, week 3 postpartum and week 6 postpartum. The results were evaluated by ANOVA consisting of the subject factor, between subject factors ICP, gestational age at the diagnosis of ICP and gestational age at labor, within-subject factor Stage and ICP × Stage interaction. The 17 controls were firstly examined in the week 36 of gestation. ICP patients showed reduced CYP17A1 activity in the C17,20 lyase step thus shifting the balance between the toxic conjugated pregnanediols and harmless sulfated 5alpha/beta-reduced-17-oxo C19 steroids. Hence, more toxic metabolites originating in maternal liver from the placental pregnanes may penetrate backward to the fetal circulation. As these alterations persist in puerperium, the circulating steroids could be potentially used for predicting the predisposition to ICP even before next pregnancy.

• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• genetická predispozice k nemoci genetika   MeSH
• intrahepatální cholestáza krev   diagnóza   genetika   MeSH
• jaterní testy trendy   MeSH
• komplikace těhotenství krev   diagnóza   genetika   MeSH
• lidé MeSH
• placentární oběh fyziologie   MeSH
• steroidy krev   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Diabetes is a well-known risk factor in pregnancy. Because maternal diabetes involves oxidative stress that is also induced by chronic hypoxia and can alter vascular function, we sought to determine the effects of chronic maternal hyperglycemia on the fetoplacental vasculature in rats and to compare it with the effects of chronic hypoxia. METHODS: Diabetes was induced in female rats by a streptozotocin injection at a neonatal age. When these animals reached adulthood, their hyperglycemia was confirmed and they were inseminated. Half of them were exposed to hypoxia (10% O2) for the last week before the delivery. One day before the expected date of delivery, one of their placentae was isolated and perfused. RESULTS: Fetoplacental vascular resistance was increased equally by experimental diabetes, chronic hypoxia, and their combination. Fetoplacental perfusion pressure-flow analysis suggested increased resistance in the small vessels in chronic hypoxia and in larger vessels in diabetes. Fetal plasma nitrotyrosine levels, measured as a marker of peroxynitrite (reaction product of superoxide and nitric oxide), mirrored the differences in fetoplacental resistance, suggesting a causative role. Fetoplacental vasoconstrictor reactivity to acute hypoxic stimuli was reduced similarly in all groups. Fasudil, a strong vasodilator agent, reduced fetoplacental vascular resistance similarly in all groups, suggesting that for the observed differences among the groups, the changes in vascular morphology were more important than variances in vascular tone. DISCUSSION: Maternal diabetes increases fetoplacental vascular resistance to a similar extent as chronic hypoxia. These stimuli are not additive. Changes in vascular tone are not responsible for these effects.

• MeSH
• cévní rezistence fyziologie   MeSH
• experimentální diabetes mellitus metabolismus   patofyziologie   MeSH
• gestační diabetes metabolismus   patofyziologie   MeSH
• hypoxie metabolismus   patofyziologie   MeSH
• krysa rodu rattus MeSH
• oxidační stres fyziologie   MeSH
• placenta krevní zásobení   MeSH
• placentární oběh fyziologie   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Typ studie: Přehledový článek. Pracoviště: Gynekologicko-porodnická klinika, 1. lékařská fakulta Univerzity Karlovy a Nemocnice Na Bulovce, Praha; Katedra fyziologie, Přírodovědecká fakulta Univerzity Karlovy, Praha; Klinika dětského a dorostového lékařství, 1. lékařská fakulta Univerzity Karlovy a Všeobecná fakultní nemocnice, Praha. Úvod: Intrauterinní růstová retardace plodu (IUGR) je jeden z největších problémů současného porodnictví. Incidence se pohybuje kolem 3–10 % podle typu studované populace a vybraných kritérií. Nejvíce používanou definicí je váha plodu pod 10. percentilem vzhledem ke gestačnímu věku. Část autorů definuje IUGR pod 5. nebo 3. percentil. Jakýkoli zásah do vývoje cévního zásobení placenty může mít kritický dopad na růst a vývoj plodu. Omezená uteroplacentární perfuze je pak nejčastější příčinou IUGR. Vznik IUGR může být také odrazem poruchy prodlužování, větvení a dilatace kapilár placenty. Metodika: Tento přehledový článek shrnuje aktuální informace týkající se změn v placentární angiogenezi a jejich vlivu na rozvoj IUGR. Závěr: Cílem je shrnout současné znalosti týkající se mechanismu vývoje vaskulárního zásobení placenty za fyziologických podmínek a za podmínek vedoucí k rozvoji IUGR. Klíčová slova: intrauterinní růstová retardace plodu, růstové faktory, placenta, váha plodu, angiogeneze

Type of study: Summary review. Setting: Department of Gynaecology and Obstetrics, 1st Faculty of Medicine, Charles University and Hospital Na Bulovce, Prague; Department of Physiology, Faculty of Science, Charles University, Prague; Department of Children and Adolescent Medicine, 1st Faculty of Medicine, Charles University in Prague and General Teaching Hospital, Prague. Introduction: Intrauterine growth restriction (IUGR) is one of the most common problems in obstetrics. Its incidence is ranging between 3–10%, according to the type of study population and chosen criteria. The cutoff value mainly used for defining the IUGR is weight below the 10th percentile for gestational age. The minority of authors defines the cutoff value under the 5th or 3rd percentile. Any pathological interference with normal vascular development of placenta may have a critical impact on foetal growth and development. Ischaemia is the most common cause of IUGR in normally well-supplied placenta. IUGR is then a consequence of insufficient extension, branching, and dilatation of capillary loops during the formation of terminal villi. Methods: This paper is a review focused on up-to-date-known data concerning changes in placental angiogenesis and their impact on IUGR development. Conclusion: The aim of this review is to summarize the knowledge concerning the mechanisms of development of the vascular supply to the placenta under physiological conditions and in conditions that result in IUGR. Keywords: intrauterine growth restriction, angiogenic factors, placenta, foetal weight, angiogenesis

• Klíčová slova
• angiogeneze,
• MeSH
• biometrie MeSH
• fyziologická neovaskularizace MeSH
• hmotnost plodu MeSH
• hypotrofický novorozenec MeSH
• hypoxie plodu diagnóza   etiologie   patofyziologie   MeSH
• komplikace těhotenství MeSH
• lidé MeSH
• patologická angiogeneze MeSH
• placenta fyziologie   krevní zásobení   patofyziologie   MeSH
• placentární insuficience etiologie   patofyziologie   ultrasonografie   MeSH
• placentární oběh * fyziologie   MeSH
• porodní hmotnost MeSH
• růstová retardace plodu * diagnóza   etiologie   patofyziologie   MeSH
• těhotenství MeSH
• ultrasonografie dopplerovská MeSH
• ultrasonografie prenatální MeSH
• vaskulární endoteliální růstové faktory MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• sEng, solubilní endoglin, PIGF, placentární protein 13,
• MeSH
• biologické markery * krev   moč   MeSH
• CD antigeny krev   MeSH
• inzulinová rezistence MeSH
• lidé MeSH
• membránové proteiny krev   moč   MeSH
• měření krevního tlaku MeSH
• placentární oběh fyziologie   MeSH
• preeklampsie * diagnóza   etiologie   prevence a kontrola   MeSH
• receptor 1 pro vaskulární endoteliální růstový faktor krev   MeSH
• receptory buněčného povrchu krev   MeSH
• rizikové faktory MeSH
• těhotenské proteiny krev   MeSH
• těhotenství MeSH
• ultrasonografie prenatální * MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH

• MeSH
• angiopoetin-2 fyziologie   MeSH
• cévy * fyziologie   růst a vývoj   MeSH
• kadheriny fyziologie   MeSH
• lidé MeSH
• oxid dusnatý fyziologie   MeSH
• placenta * krevní zásobení   MeSH
• placentární oběh fyziologie   MeSH
• těhotenské proteiny * fyziologie   krev   MeSH
• těhotenství MeSH
• trimestry těhotenství MeSH
• vaskulární endoteliální růstové faktory fyziologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH

The increased fetoplacental vascular resistance due to chronic hypoxia cannot be explained by simple hypoxic vasoconstriction, as it sustains to some degree after recovery in normobaric environment. To verify a hypothesis that fetoplacental arteries undergo remodeling of their walls similar to remodeling of pulmonary arteries in hypoxic pulmonary hypertension, we used a model of the chronically hypoxic rat placenta. Han Wistar pregnant rats were exposed to 14-day hypoxia (10% of oxygen) during the 6th to 19th day of pregnancy. Chronic hypoxia elicited in both intraplacental (prelabyrinthine) and chorionic plate (insertion) arteries significant narrowing of their lumina. Irregular thickening of their adventitia due to an increase in collagen fibers as well as ground substance was observed; reticular fibers were fragmented. Because of remodeling of fetoplacental arteries, a model of chronically hypoxic rat placenta could simulate human preplacental hypoxia and consequent effects.

• MeSH
• arteriae umbilicales patofyziologie   ultrastruktura   MeSH
• cévní rezistence MeSH
• chorion * krevní zásobení   ultrastruktura   MeSH
• hypoxie patologie   patofyziologie   MeSH
• inbrední kmeny potkanů MeSH
• komplikace těhotenství patologie   patofyziologie   MeSH
• krysa rodu rattus MeSH
• placenta * krevní zásobení   ultrastruktura   MeSH
• placentární oběh fyziologie   MeSH
• těhotenství MeSH
• transmisní elektronová mikroskopie MeSH
• vazokonstrikce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH