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Biomedical subjects

Leslie Myatt

Publications and source records attributed to Leslie Myatt.

18 recordsLinked to original sources
PubMed2006

Induction of surfactant protein A expression by cortisol facilitates prostaglandin synthesis in human chorionic trophoblasts.

CONTEXT: Surfactant protein A (SP-A) may be an important link between the maturation of fetal organs and the initiation of parturition. However, the local expression of SP-A and the effect of SP-A on prostaglandin synthesis in human fetal membranes have not been resolved. OBJECTIVE: Our objective was to examine SP-A expression and the effect of SP-A on prostaglandin synthesis in human fetal membranes. DESIGN: SP-A expression was examined with immunohistochemistry and PCR. The effect of SP-A on prostaglandin synthesis was investigated in cultured human chorionic trophoblasts. PATIENTS: Patients were normal-term pregnant women undergoing elective cesarean sections. RESULTS: Both SP-A protein and mRNA were present in amnion epithelial cells, fibroblasts, and chorionic trophoblasts. Cortisol (10(-7) and 10(-6) M, 24 h) induced SP-A expression in cultured chorionic trophoblasts, which could be blocked by the glucocorticoid receptor antagonist RU486. Treatment of chorionic trophoblasts with SP-A (10-100 microg/ml, 24 h) caused a dose-dependent increase of prostaglandin E2 release and an induction of cyclooxygenase type 2 but not cytosolic phospholipase A2 and microsomal prostaglandin E synthase expression. CONCLUSIONS: SP-A can be synthesized locally in human fetal membranes, which can be induced by glucocorticoids. SP-A appeared to induce prostaglandin E2 synthesis in chorionic trophoblasts via induction of cyclooxygenase type 2 expression.

Cells, Cultured↗
PubMed2006

Regional expression of prostaglandin E2 and F2alpha receptors in human myometrium, amnion, and choriodecidua with advancing gestation and labor.

The change from uterine quiescence to enhanced contractile activity may be due to the differential expression of prostaglandin receptors within the myometrium and fetal membranes, in a temporal and topographically distinct manner. To address this question, we determined the localization and expression of the PGE2 receptor subtypes (PTGER1-4) and the PGF2alpha receptor (PTGFR) in paired upper and lower segment myometrium, amnion, and choriodecidual samples throughout human pregnancy, with and without labor. All receptor subtypes were found throughout the muscle layers in both the upper and lower uterine segments, colocalizing with alpha smooth muscle actin. A change in intracellular localization was observed at term labor, where PTGER1 and PTGER4 were predominately associated with the nucleus. Minimal changes in the expression of the PGE2 and PGF2alpha receptor subtypes were observed with gestational age, labor, or between the upper and lower myometrial segments. Receptor expression in maternal and fetal tissues differed between the receptor subtypes; PTGER1 and PTGER4 were predominately expressed in the fetal membranes, PTGER2 was greatest in the myometrium, whereas PTGER3 and PTGFR were similarly expressed in the myometrium and fetal membranes. Myometrial activation through the prostaglandin receptors is perhaps more subtle and may be mediated by a balance between one or several of the prostaglandin receptor subtypes together with other known contraction associated proteins. Lack of coordination in receptor expression between the myometrium and fetal membranes may indicate different regulatory mechanisms between these tissues, or it may suggest a function for these receptors in the amnion and choriodecidua that is independent of that seen in the myometrium.

Amnion↗
PubMed2006

Localization and expression of prostaglandin E2 receptors in human placenta and corresponding fetal membranes with labor.

OBJECTIVE: The effects of prostaglandin E2 (PGE2) are mediated through G-protein coupled receptors, acting via different second messengers. The aim of this study was to characterize the temporal and tissue specific localization and expression of the PGE2 receptor subtypes (EP1-4) in uteroplacental tissues during human pregnancy. STUDY DESIGN: Placenta and fetal membranes were collected after delivery at preterm or term, each with or without labor. The localization and expression of the PGE2 receptor subtypes were determined by immunohistochemistry and Western blot. RESULTS: All 4 receptors were expressed in the placenta and fetal membranes; only EP3 was present in the syncytiotrophoblast layer. EP1 to EP4 were consistently expressed across gestation in the fetal membranes; however, a different cellular localization with labor was observed in the amnion for EP1, EP2, and EP4. CONCLUSION: The presence of these receptors in the placenta and fetal membranes may indicate autocrine roles for PGE2 in the signaling pathways associated with placental function and parturition.

Adult↗
PubMed2006

Placental adaptive responses and fetal programming.

Fetal programming occurs when the normal pattern of fetal development is disrupted by an abnormal stimulus or 'insult' applied at a critical point in in utero development. This then leads to an effect, for example diabetes or hypertension, which manifests itself in adult life. As the placenta is the regulator of nutrient composition and supply from mother to fetus and the source of hormonal signals that affect maternal and fetal metabolism, appropriate development of the placenta is crucial to normal fetal development. Placental function evolves in a carefully orchestrated developmental cascade throughout gestation. Disruption of this cascade can lead to abnormal development of the placental vasculature or of the trophoblast. Timing of a developmental 'insult' will be critical in consequent placental function and hence programming of the fetus. The 'insults' that alter placental development include hypoxia and abnormal maternal nutrient status, to which the placenta may adapt by alterations in transporter expression and activity to maintain fetal growth or by epigenetic regulation of placental gene expression. Hypoxia is physiological for organogenesis and placental tissue normally exists in a relatively hypoxic environment, but intrauterine growth restriction (IUGR) and pre-eclampsia are associated with a greater degree of trophoblast hypoxia. The metabolic activity of placental mitochondria leads to oxidative stress even in normal pregnancy which is exacerbated further in IUGR, diabetic and pre-eclamptic pregnancies and may also give nitrative stress known to lead to covalent modification and hence altered activity of proteins. Hypoxia, oxidative and nitrative stress all alter placenta development and may be a general underlying mechanism that links altered placental function to fetal programming.

Adaptation, Physiological↗
PubMed2006

Enhancement of cortisol-induced 11beta-hydroxysteroid dehydrogenase type 1 expression by interleukin 1beta in cultured human chorionic trophoblast cells.

Chorion is the most abundant site of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expression within intrauterine tissues. It is important to study the regulation of 11beta-HSD1 expression in the chorion in terms of local cortisol production during pregnancy. Using real-time PCR and enzyme activity assay, we found that cortisol (1 mum) and IL-1beta (10 ng/ml) for 24 h significantly increased 11beta-HSD1 mRNA expression and reductase activity in cultured human chorionic trophoblasts. A further significant increase of 11beta-HSD1 mRNA expression and reductase activity was observed with cotreatment of cortisol and IL-1beta. To explore the mechanism of induction, 11beta-HSD1 promoter was cloned into pGL3 plasmid expressing a luciferase reporter gene. By transfecting the constructed vector into WISH cells, an amnion-derived cell line, we found that cortisol (1 microM) or IL-1beta (10 ng/ml) significantly increased reporter gene expression. Likewise, an additional increase in reporter gene expression was observed with cotreatment of cortisol and IL-beta. To explore the physiological significance of 11beta-HSD1 induction in the chorion, we studied the effect of cortisol on cytosolic phospholipase A(2) and cyclooxygenase 2 expression. We found that treatment of chorionic trophoblast cells with cortisol (1 microM) induced both cytosolic phospholipase A(2) and cyclooxygenase 2 mRNA expression. We conclude that cortisol up-regulates 11beta-HSD1 expression through induction of promoter activity, and the effect was enhanced by IL-1beta, suggesting that more biologically active glucocorticoids could be generated in the fetal membranes in the presence of infection, which may consequently feed forward in up-regulation of prostaglandin synthesis.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Peroxynitrite treatment in vitro disables catalytic activity of recombinant p38 MAPK.

Protein tyrosine nitration is a post-translational modification occurring under conditions of oxidative stress in a number of diseases. The causative agent of tyrosine nitration is the potent prooxidant peroxynitrite that results from the interaction of nitric oxide and superoxide. We have previously demonstrated existence of nitrotyrosine in placenta from pregnancies complicated by preeclampsia, which suggested the possibility of the existence of nitrated proteins. Nitration of various proteins has been demonstrated to more commonly result in loss of protein function. Potential nitration of p38 MAPK, a critical signaling molecule has been suggested and also tentatively identified in certain in vivo systems. In this study we demonstrate for the first time nitration of recombinant p38 MAPK in vitro and an associated loss of its catalytic activity. LC-MS data identified tyrosine residues Y132, Y245 and Y258 to be nitrated. Nitration of these specific residues was deduced from the 45.0-Da change in mass that these residues exhibited that was consistent with the loss of a proton and addition of the nitro group.

Amino Acid Sequence↗
PubMed2005

Expression and localization of adipophilin and perilipin in human fetal membranes: association with lipid bodies and enzymes involved in prostaglandin synthesis.

Lipid storage droplets (LSDs) are subcellular storage depots for triglycerides (TGs) and cholesterol esters surrounded by specific populations of proteins that are necessary for their formation. We have previously described the appearance of LSDs in human fetal membranes with advancing gestation and labor. Perilipin and adipophilin are functional/structural proteins located on the surfaces of intracellular LSDs. Adipophilin and perilipin were both immunolocalized to the amnion epithelium and amnion fibroblasts in human fetal membranes. Adipophilin was also localized to the choriodecidual layer, whereas perilipin was localized to the chorion trophoblasts. Although immunohistochemical data show an apparent increase in adipophilin, but not perilipin, expression in fetal membranes with advancing gestation and labor, Western analysis of tissue homogenate supernatant revealed no significant changes in adipophilin and perilipin expression. However, Western analysis of the floating lipid-rich layer from the tissue homogenate revealed an abundance of adipophilin and perilipin as well as other enzymes (cytosolic phospholipase A2, prostaglandin endoperoxide, and microsomal-associated prostaglandin E synthase-1) involved in prostaglandin synthesis. The association of these enzymatically active proteins with LSDs suggests that LSDs may be foci for signaling via the arachidonic acid cascade in fetal membranes. The structural and functional roles of adipophilin and perilipin in gestation and labor remain to be determined.

Animals↗
PubMed2005

Heat shock protein-70 and 4-hydroxy-2-nonenal adducts in human placental villous tissue of normotensive, preeclamptic and intrauterine growth restricted pregnancies.

OBJECTIVE: The purpose of this study was to compare immunohistochemical expression of heat shock protein-70 (hsp70), a marker for oxidative stress, and 4-hydroxy-2-nonenal adducts (HNE), a marker for lipid peroxidation, in placental villous tissue of normotensive, preeclampsia, and intrauterine growth restricted (IUGR) pregnancies. STUDY DESIGN: Placentas were collected and flash frozen in liquid nitrogen after delivery from normotensive pregnancies (n=5), and pregnancies complicated by preeclampsia (n=5), IUGR (n=5), and preeclampsia plus IUGR (n=4). Cryosections were cut and immunostained with polyclonal anti-hsp70 and monoclonal anti-HNE antibodies using Vectastain Elite ABC kit. Normal rabbit serum or mouse IgG were used as negative controls. Three independent observers, blinded to identity of tissue, examined each slide to identify cellular localization and intensity of the immunostaining. Western blot analysis and scanning densitometry were used to quantify and compare the amount of hsp70 and HNE adducts present in tissue homogenates. RESULTS: Positive immunostaining for both antibodies was observed in cytoplasm of syncytiotrophoblasts, extravillous trophoblasts, vascular smooth muscle, and endothelial cells for all groups. Expression of hsp70 and HNE adducts was reported as observers' mean stained intensity. Overall, kappa showed good agreement between observers. Immunostaining intensity was similar in all tissue types for each group with the exception that immunostaining was significantly more intense in the vascular endothelium of the preeclamptic group for HNE adducts (P=.02) and significantly less intense in the IUGR group for hsp70 (P=.013). Scanning densitometric analysis of the Western blots showed no significant difference in total hsp70 and HNE adducts expression in all 4 tissue groups. CONCLUSION: Immunohistochemistry showed local changes for oxidative stress and lipid peroxidation in the vascular endothelium from placentas of preeclamptic and IUGR pregnancies. However, these changes were masked when studying tissue homogenates.

Aldehydes↗
PubMed2004

Oxidative stress in the placenta.

Pregnancy is a state of oxidative stress arising from increased placental mitochondrial activity and production of reactive oxygen species (ROS), mainly superoxide anion. The placenta also produces other ROS including nitric oxide, carbon monoxide, and peroxynitrite which have pronounced effects on placental function including trophoblast proliferation and differentiation and vascular reactivity. Excessive production of ROS may occur at certain windows in placental development and in pathologic pregnancies, such as those complicated by preeclampsia and/or IUGR, overpowering antioxidant defenses with deleterious outcome. In the first trimester, establishment of blood flow into the intervillous space is associated with a burst of oxidative stress. The inability to mount an effective antioxidant defense against this results in early pregnancy loss. In late gestation increased oxidative stress is seen in pregnancies complicated by diabetes, IUGR, and preeclampsia in association with increased trophoblast apoptosis and deportation and altered placental vascular reactivity. Evidence for this oxidative stress includes increased lipid peroxides and isoprostanes and decreased expression and activity of antioxidants. The interaction of nitric oxide and superoxide produces peroxynitrite, a powerful prooxidant with diverse deleterious effects including nitration of tyrosine residues on proteins thus altering function. Nitrative stress, subsequent to oxidative stress is seen in the placenta in preeclampsia and diabetes in association with altered placental function.

Antioxidants↗
PubMed2004

Expression, localization and function of prostaglandin receptors in myometrium.

Prostaglandins (PGs) play a role in the initiation and maintenance of labor, acting via specific relaxatory or contractile receptors on myometrium. Myometrial response to addition of PGs may be determined by the type and concentration of receptor expressed. Autoradiographic and ligand binding studies suggest a topographic distribution of receptors between fundus, lower segment, and cervix, and that hormonally regulated changes in expression occur with advancing gestation and labor. These receptors have now been cloned and sequenced allowing molecular studies. Current dogma suggests functional regionalization of the pregnant human uterus occurs with the lower segment displaying a contractile phenotype throughout gestation changing to a relaxatory phenotype at labor to allow passage of the fetal head whereas the upper segment has a relaxatory phenotype throughout most of gestation to accommodate the growing fetus and adopts a contractile phenotype for expulsion at labor. Studies to determine the role of PG receptors in this phenomenon are currently underway.

Animals↗
PubMed2003

Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway.

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E2 synthase-1 (mPGES-1) as a RET/PTC-inducible gene through subtraction hybridization cloning and expression profiling with custom microarrays. The inducible prostaglandin E2 (PGE2) biosynthetic enzymes cyclooxygenase-2 (COX-2) and mPGES-1 are up-regulated in many cancers. COX-2 is overexpressed in thyroid malignancies compared with benign nodules and normal thyroid tissues. Eicosanoids may promote tumorigenesis through effects on tumor cell growth, immune surveillance, and angiogenesis. Conditional RET/PTC1 or RET/PTC3 expression in PCCL3 thyroid cells markedly induced mPGES-1 and COX-2. PGE2 was the principal prostanoid and up-regulated (by approximately 60-fold), whereas hydroxyeicosatetraenoic acid metabolites were decreased, consistent with shunting of prostanoid biosynthesis toward PGE2 by coactivation of the two enzymes. RET/PTC activated mPGES-1 gene transcription. Based on experiments with kinase inhibitors, with PCCL3 cell lines with doxycycline-inducible expression of RET/PTC mutants with substitutions of critical tyrosine residues in the kinase domain, and lines with inducible expression of activated mutants of H-RAS and MEK1, RET/PTC was found to regulate mPGES-1 through Shc-RAS-MEK-ERK. These data show a direct relationship between activation of a tyrosine kinase receptor oncogene and regulation of PGE2 biosynthesis. As enzymes involved in prostanoid biosynthesis can be targeted with pharmacological inhibitors, these findings may have therapeutic implications.

Animals↗
PubMed2003

Enhancement of glucocorticoid-induced 11beta-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts.

Glucocorticoids and proinflammatory cytokines may be involved in parturition by stimulation of prostaglandin production in the fetal membranes. The actions of glucocorticoids on the fetal membranes are amplified by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which converts biologically inactive cortisone into active cortisol. Whether glucocorticoids and proinflammatory cytokines regulate the expression of 11beta-HSD1 in the major prostaglandin-producing tissue, amnion, thus further increasing prostaglandin production, is not known. In this study, we found that term amnion fibroblasts had higher 11beta-HSD1 mRNA and activity per cell than amnion epithelial cells. Both isoforms of glucocorticoid receptor (alpha and beta) were expressed in amnion fibroblasts and epithelial cells. Quantitative real-time PCR showed that dexamethasone (0.01-1 microm) dose-dependently induced 11beta-HSD1 mRNA expression only in amnion fibroblasts but not in amnion epithelial cells. The induction of 11beta-HSD1 mRNA expression by dexamethasone was blocked by glucocorticoid receptor antagonist RU486. Although only a modest increase or no change in 11beta-HSD1 mRNA expression and activity was observed with IL-1beta (10 ng/ml) or TNFalpha (10 ng/ml) treatment, respectively, in amnion fibroblasts, combination of dexamethasone with either IL-1beta or TNFalpha significantly enhanced the induction of 11beta-HSD1 mRNA expression and activity, as compared with dexamethasone treatment alone. With prior induction of 11beta-HSD1 expression by dexamethasone, cortisone caused more prostaglandin E2 production in the amnion fibroblast. This study suggests that glucocorticoids can positively induce 11beta-HSD1 expression in amnion fibroblasts, an effect further strengthened by proinflammatory cytokines.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

Transport of cholesterol across a BeWo cell monolayer: implications for net transport of sterol from maternal to fetal circulation.

The placental transport of various compounds, such as glucose and fatty acids, has been well studied. However, the transport of cholesterol, a sterol essential for proper fetal development, remains undefined in the placenta. Therefore, the purpose of these studies was to examine the transport of cholesterol across a placental monolayer and its uptake by various cholesterol acceptors. BeWo cells, which originated from a human choriocarcinoma, were grown on transwells for 3 days to form a confluent monolayer. The apical side of the cells was radiolabeled with either free cholesterol or LDL cholesteryl ester. After 24 h, the radiolabel was removed and cholesterol acceptors were added to the basolateral chamber. Cholesterol was found to be taken up by the apical surface of the placental monolayer, transported to the basolateral surface of the cell, and effluxed to fetal human serum, fetal HDL, or phospholipid vesicles, but not to apolipoprotein A-I. In addition, increasing the cellular cholesterol concentration further increased the amount of cholesterol transported to the basolateral acceptors. These are the first studies to demonstrate the movement of cholesterol across a placental cell from the maternal circulation (apical side) to the fetal circulation (basolateral side).

Apolipoprotein A-I↗
PubMed2003

P2Y2 receptor-stimulated release of prostaglandin E2 by rat inner medullary collecting duct preparations.

Extracellular nucleotides, acting through the P2Y2 receptor and the associated phosphoinositide-Ca2+ signaling pathway, inhibit AVP-stimulated osmotic water permeability in rat inner medullary collecting duct (IMCD). Because a rise in intracellular Ca2+ is frequently associated with enhanced arachidonic acid metabolism, we examined the effect of activation of the P2Y2 receptor on release of PGE2 in freshly prepared rat IMCD suspensions. Unstimulated IMCD released moderate, but significant, amounts of PGE2, which were more sensitive to cyclooxygenase (COX)-2 than COX-1 inhibition. Agonist activation of P2Y2 receptor by adenosine 5'-O-(3-thiotriphosphate) enhanced release of PGE2 from IMCD in a time- and concentration-dependent fashion. Purinergic-stimulated release of PGE2 was completely blocked by nonspecific COX inhibitors (flurbiprofen and 2-acetoxyphenylhept-2-ynyl sulfide). Differential COX inhibition studies revealed that purinergic-stimulated release of PGE2 was more sensitive to a COX-1-specific inhibitor (valeroyl salicylate) than a COX-2-specific inhibitor (NS-398). Thus purinergic stimulation resulted in significantly more release of PGE2 in the presence of COX-2 inhibitor than COX-1 inhibitor. If it is assumed that increased release of PGE2 is related to its increased production, our results suggest that purinergic stimulation of IMCD results in enhanced production and release of PGE2 in a COX-1-dependent fashion. Because PGE2 is known to affect transport of water, salt, and urea in IMCD, interaction of the purinergic system with the prostanoid system in IMCD can modulate handling of water, salt, and urea by IMCD and, thus, may constitute an AVP-independent regulatory mechanism.

Adenosine Triphosphate↗
PubMed2003

Expression and localization of prostaglandin E synthase isoforms in human fetal membranes in term and preterm labor.

Increased prostaglandin (PG) synthesis by fetal membranes occurs at parturition. PGE(2) synthesis from arachidonic acid involves multiple enzymes and two isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the heat shock protein 90 chaperone, p23, and is reportedly functionally coupled to constitutive PG endoperoxide H synthase-1. Microsomal PGES (mPGES) is inducible by proinflammatory cytokines such as IL-1 beta. We have studied expression and localization of both enzyme isoforms in human fetal membranes either at term or preterm, with or without labor. The cPGES was immunolocalized in the amnion epithelium, and associated with fibroblasts and macrophages in the choriodecidual layer, whereas mPGES was localized in the amnion epithelium as well as the chorion trophoblast. Both enzymes were found to be associated with lipid particles present in the amnion epithelium, which are more prevalent in term tissues. Western blot analysis of the amnion and choriodecidua showed no differences in amounts of either cPGES or mPGES at term or preterm, with or without labor, in either tissue with advancing gestation. It does not appear that expression of PGES is the rate-limiting step in PGE2 synthesis in fetal membranes at labor.

Amnion↗
PubMed2003

Glucocorticoids induce cytosolic phospholipase A2 and prostaglandin H synthase type 2 but not microsomal prostaglandin E synthase (PGES) and cytosolic PGES expression in cultured primary human amnion cells.

This study examines the regulation of major enzymes in prostaglandin E(2) (PGE(2)) synthesis by glucocorticoids in separate cultures of human amnion epithelial and fibroblast cells at term. Cytosolic phospholipase A(2) (cPLA(2)), cytosolic PGES (cPGES), and microsomal PGES (mPGES) mRNA were expressed at similar levels in both cell types, whereas a greater prostaglandin H synthase type 2 (PGHS-2) mRNA expression was observed in amnion fibroblasts than in epithelial cells. Amnion fibroblasts produced 50-fold more PGE(2) per cell than epithelial cells. Dexamethasone (0.01-1 microM) increased PGE(2) production in amnion fibroblasts in a concentration-dependent manner but did not affect PGE(2) production in amnion epithelial cells. Both mRNA and protein expression of cPLA(2) and PGHS-2 but not cPGES and mPGES were increased in a dose-dependent manner by dexamethasone (0.01-1 microM) in amnion fibroblasts. Induction of cPLA(2) and PGHS-2 mRNA by dexamethasone was blocked by RU486. Dexamethasone did not affect PGHS-2, cPGES, and mPGES mRNA expression in amnion epithelial cells. In conclusion, amnion fibroblasts express a higher level of PGHS-2 mRNA and produced more PGE(2) per cell than amnion epithelial cells at term of human pregnancy. Glucocorticoids increase PGE(2) production only in the amnion fibroblasts mainly through induction of cPLA(2) and PGHS-2 expression.

Amnion↗
PubMed2002

Role of placenta in preeclampsia.

Preeclampsia, which manifests itself as hypertension, proteinuria, and edema in pregnancy, requires the presence of trophoblast tissue but not a fetus. It is characterized by abnormal trophoblast invasion of the spiral arteries of the decidua and myometrium leading to a failure to establish an adequate uteroplacental blood flow and, therefore, is thought to give rise to relatively hypoxic trophoblast tissue. This, in turn, may promote an exaggerated state of oxidative stress in the placenta. This hypoxia/oxidative stress may then further attenuate trophoblast invasion but also alters placental villous angiogenesis leading to a poorly developed fetoplacental vasculature with abnormal reactivity. Oxidative stress per se may also affect vascular reactivity, blood flow, and oxygen and nutrient delivery to the fetus, which ultimately may be compromised. The synthetic and transport functions of the syncytiotrophoblast may also be altered, and there is an increased rate of trophoblast apoptosis. The linkage among abnormal trophoblast invasion, trophoblast dysfunction, and the maternal disease remains unidentified. The presumptive humoral factor that is released by the preeclamptic placenta to cause maternal disease remains elusive. Current therapies to prevent preeclampsia aim toward preventing the maternal syndrome, not preventing the primary pathophysiology.

Apoptosis↗