Developing and Validating a Simple Risk Score for Patients with Acute Myocardial Infarction.

INTRODUCTION: Mortality from acute myocardial infarction (AMI) remains substantial. The current study is aimed at developing a novel simple risk score for AMI. METHODS: The Coronary Artery Tree description and Lesion EvaluaTion (CatLet) extended validation trial (ChiCTR2000033730) and the CatLet validation trial (ChiCTR-POC-17013536), both being registered with chictr.org, served as the derivation and validation datasets, respectively. Both datasets included 1,018 and 308 patients, respectively. They all suffered from AMI and underwent percutaneous intervention (PCI). The endpoint was 4-year all-cause death. Lasso regression analysis was used for covariate selection and coefficient estimation. RESULTS: Of 26 candidate predictor variables, the four strongest predictors for 4-year mortality were included in this novel risk score with an acronym of BACEF (serum alBumin, Age, serum Creatinine, and LVEF). This score was well calibrated and yielded an AUC (95% CI) statistics of 0.84 (0.80-0.87) in internal validation, 0.89 (0.83-0.95) in internal-external (temporal) validation, and 0.83 (0.77-0.89) in external validation. Notably, it outperformed the ACEF, ACEF II, GRACE scores with respect to 4-year mortality prediction. CONCLUSION: A simple risk score for 4-year mortality risk stratification was developed, extensively validated, and calibrated in patients with AMI. This novel BACEF score may be a useful risk stratification tool for patients with AMI.

Characterization of the lncRNA-mediated ceRNA regulatory networks in preeclampsia by integrated bioinformatics.

Preeclampsia (PE) is a significant threat to all pregnancies that is highly associated with maternal mortality and developmental disorders in infants. However, the etiopathogenesis of this condition remains unclear. This study aims to explore the regulatory roles of long noncoding RNAs (lncRNAs) and the mediated competing endogenous RNAs (ceRNA) in the etiopathogenesis of PE through analysis of lncRNA expression patterns in PE and healthy pregnant women (HPW), as well as the construction of lncRNA-mediated ceRNA regulatory networks using bioinformatics. A total of 896 significant differentially expressed lncRNAs, including 586 upregulated lncRNAs and 310 downregulated lncRNAs, were identified in comparison between PE and HPW. Analysis of these differential expressed lncRNAs revealed their predominant enrichment in molecular functions such as sphingosine-1-phosphate phosphatase activity, lipid phosphatase activity, phosphatidate phosphatase activity, thymidylate kinase activity, and UMP kinase activity. Moreover, these differential expressed lncRNAs were predominantly enriched in KEGG analyses such as fat digestion and absorption, lysine degradation, ether lipid metabolism, glycerolipid metabolism, and sphingolipid metabolism. Two ceRNA regulatory networks were constructed based on ceRNA score, including one that had 31 upregulated lncRNAs, 11 downregulated miRNAs, and 34 upregulated mRNAs, while the other contained 128 downregulated lncRNAs, 40 upregulated miRNAs, and 113 downregulated mRNAs. These results may provide a clue to explore the roles of lncRNAs in the etiopathogenesis of PE.

In vitro fertilization with frozen embryo transfer increased histamine-mediated contractile sensitivity via PKCß in human umbilical vein.

OBJECTIVE: In vitro fertilization-embryo transfer (IVF-ET) technologies (especially frozen ET) have been widely used, which might affect maternal and fetal health. Information regarding influence of IVF-ET on the vasoconstriction of human umbilical vein (HUV) is limited. This study determined effects of frozen ET on histamine-mediated vascular responses in HUV and related mechanisms. METHODS AND RESULTS: HUVs were collected from frozen ET conceived pregnancy and spontaneously conceived pregnancy (control). Histamine concentration in umbilical plasma was higher in frozen ET group than the control. Histamine-mediated contractile response curve was left-shifted in the frozen ET group when comparing with the control. In isolated HUV rings, H1R showed a critical role in regulating vascular constriction, while H2R played little roles in regulating vessel tone. Iberiotoxin and 4-aminopyridine didn't significantly change histamine-mediated constriction in HUVs. Histamine-induced vasoconstrictions were significantly decreased by nifedipine, KN93, or GF109203X, while the inhibitory effects were significantly greater in the frozen ET group in comparison to the control. The constrictions by Bay K8644, phenylephrine, or PDBu were stronger in frozen ET, respectively. There was a decrease in the protein expressions of H1R and H2R, an increase in protein expressions of BKCaα and PKCß. CONCLUSIONS: Histamine-induced constriction in HUV was mainly via H1R. The increased sensitivity to histamine in HUV following frozen ET cycles were linked to the enhanced PKCß protein expression and function. The new data and findings in this study provide important insight into influences of frozen ET on fetal vessel development and potential influence in long-term.

Specific dilation pattern in placental circulation and the NO/sGC role in preeclampsia placental vessels.

Objective: Endothelial functions in controlling blood flow in placental circulation are still unclear. The present study compares vascular dilations between placental circulation and other vessels, as well as between normal and preeclampsia placental vessels. Methods: Placental, umbilical, and other vessels (cerebral and mesenteric arteries) were collected from humans, sheep, and rats. Vasodilation was tested by JZ101 and DMT. Q-PCR, Western blot, and Elisa were used for molecular experiments. Results: Endothelium-dependent/derived vasodilators, including acetylcholine, bradykinin, prostacyclin, and histamine, mediated no or minimal dilation in placental circulation, which was different from that in other vessels in sheep and rats. There were lower mRNA expressions of muscarinic receptors, histamine receptors, bradykinin receptor 2, endothelial nitric oxide synthesis (eNOS), and less nitric oxide (NO) in human umbilical vessels when compared with placental vessels. Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. The sGC inhibitor ODQ suppressed the reduced baseline caused by the SNP. The decreased baseline by SNP or Bay41-2272 was higher in placental vessels than in umbilical vessels, suggesting that the role of NO/sGC is more important in the placenta. NO concentrations in preeclampsia placental vessels were lower than those in control, while no significant change was found in umbilical plasma between the two groups. eNOS expression was similar between normal and preeclampsia placental vessels, but phosphorylated eNOS levels were significantly lower in preeclampsia. Following serotonin, SNP or Bay41-2272-mediated dilations were weaker in preeclampsia placental vessels. The decreased amplitude of SNP- or Bay41-2272 at baseline was smaller in preeclampsia. The decreased amplitudes of ODQ + SNP were comparable between the two groups. Despite higher beta sGC expression, sGC activity in the preeclampsia placenta was lower. Conclusion: This study demonstrated that receptor-mediated endothelium-dependent dilation in placental circulation was significantly weaker than other vessels in various species. The results, showed firstly, that exogenous NO played a role in regulating the baseline tone of placental circulation via sGC. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels.

Prenatal hypoxia induced ETBR activation and abnormal ROS signalling in pulmonary artery cells of rat offspring.

Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O2 from gestational day 4-21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETAR/ETBR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETBR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETBR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETBR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETBR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETBR/Nox1/4-derived ROS pathway.

Interaction of lipoprotein(a) with low-density lipoprotein cholesterol on first incident acute myocardial infarction.

OBJECTIVE: To evaluate the interaction effects between lipoprotein (a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) on first incident acute myocardial infarction (AMI) among Chinese Han population. METHODS: 1522 cases and 1691 controls were retrospectively analyzed. All subjects were grouped by Lp(a) or LDL-C level. RESULTS: Compared with reference group (LDL-C < 2.6 mmol/L and in the 1st quintile of Lp(a)), multivariable-adjusted analysis revealed that OR(95%CI) of first incident AMI for higher LDL-C alone is 2.66(1.78-3.98); that ORs(95%CI) for higher Lp(a) alone are 1.51(1.07-2.15), 1.84(1.28-2.64), 1.86(1.30-2.67) and 2.66(1.88-3.76) across the Lp(a) quintiles; and that ORs(95%CI) for both higher LDL-C and higher Lp(a) are 3.95(2.64-5.92), 3.20(2.21-4.64), 5.64(3.80-8.36) and 7.48(4.90-11.44) which were greater than the sum of the risks of both alone across the Lp(a) quintiles. Relative excess risks due to interaction were 1.78(95% CI, 0.12-3.44, P = 0.036) and 3.01(0.58-5.44, P = 0.015) at the 4th and 5th quintile of Lp(a), confirming the presence of additive interaction between Lp(a) and LDL-C on initial AMI. CONCLUSIONS: Lp(a) interacts with LDL-C in first incident AMI on additive scale in Chinese Han population. The risk of initial AMI from exposure of elevated Lp(a) combined with elevated LDL-C is much greater than the sum of the risks from that of both alone.

Comparison of Vascular Responses to Vasoconstrictors in Human Placenta in Preeclampsia between Preterm and Later Term.

BACKGROUND: Placental blood vessels play important roles in maternal-fetal circulation. Although pathologic mechanisms of preeclampsia are unclear, it is known that placental vascular dysfunction could contribute to pregnant hypertension. However, placental micro-vessel function or dysfunction at preterm has not been investigated. METHODS: Human placentas from normal and preeclamptic pregnancies at preterm and term were obtained. Placental micro-vessels were used for determining vascular tension and responses to various vasoconstrictors as well as intracellular calcium store capability. It was the first time to show vascular responses in placental arteries to angiotensin II, endothelin-1, and other vascular drugs at preterm. RESULTS: Compared to the control, placental vascular contractile responses to angiotensin II and caffeine were significantly decreased, while placental vascular responses to KCl, endothelin-1, and bradykinin were not significantly altered in the later term group in preeclampsia. In comparison of placental micro-vessel tension between the preterm and later term, caffeine- and serotonin-induced vascular contractions were significantly weaker in the preterm than that in the later term. On the contrary, vascular response to angiotensin II was increased in the preterm preeclampsia, while KCl-, endothelin-1, and bradykinin-mediated placental vessel responses in the preterm preeclampsia were similar to that in later term preeclampsia. CONCLUSION: New data showed that micro-vessel responses to angiotensin II and serotonin, not endothelin- 1 or bradykinin, were significantly reduced in the human placentas at preterm, and intracellular Ca2+ store capacity was damaged too, providing important information on possible contributions of placental vascular dysfunction to pregnant hypertension.

Methylation-reprogrammed AGTR1 results in increased vasoconstriction by angiotensin II in human umbilical cord vessel following in vitro fertilization-embryo transfer.

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.

Hyper-methylation of AVPR1A and PKCΒ gene associated with insensitivity to arginine vasopressin in human pre-eclamptic placental vasculature.

BACKGROUND: Pre-eclampsia is a leading cause of maternal mortality and morbidity. Although the exact mechanisms that cause pre-eclampsia remain unclear, it is undeniable that abnormal placental function and circulation are a center for initiation pre-eclampsia. As a potent vasoconstrictor, arginine vasopressin (AVP) has long been implicated in controlling placental vascular tone and circulation; its secretion is grossly elevated in pre-eclamptic circulation. However, little is known about the reactivity of AVP in pre-eclamptic placental vasculature. METHODS: To reveal the special features of placental vascular regulations with placental pathophysiological changes, as well as the corresponding molecular mechanisms under pre-eclamptic conditions, vascular function and molecular assays were conducted with placental vessel samples from normal and pre-eclamptic pregnancies. FINDINGS: The present study found that vasoconstriction responses of placental vessels to AVP were attenuated in pre-eclampsia as compared to in normal pregnancy. The insensitivity of AVP was correlated with the down-regulated AVP receptor 1a (AVPR1A, AVPR1A gene) and protein kinase C isoform ß (PKCß, PKCΒ gene), particularly the hyper-methylation-mediated AVPR1A and PKCΒ gene down-regulation, respectively. INTERPRETATION: The findings collectively revealed that aberrant DNA methylation-mediated gene expressions are correlated with vascular dysfunction in pre-eclamptic placental circulation. FUND: This work was supported by National Nature & Science Foundation of China. "333 Project", "Six one project", "Shuang Chuang Tuan Dui" and Key Discipline "Fetal medicine" of Jiangsu Province, and the Suzhou city "Wei Sheng Ren Cai" program.

Promoter methylation changes and vascular dysfunction in pre-eclamptic umbilical vein.

BACKGROUND: Hypertension is one of primary clinical presentations of pre-eclampsia. The occurrence and progress of hypertension are closely related to vascular dysfunction. However, information is limited regarding the pathological changes of vascular functions in pre-eclamptic fetuses. Human umbilical cord vein was used to investigate the influence of pre-eclampsia on fetal blood vessels in this study. RESULTS: The present study found that the vasoconstriction responses to arginine vasopressin (AVP) and oxytocin (OXT) were attenuated in the pre-eclamptic umbilical vein as compared to in normal pregnancy, which was related to the downregulated AVP receptor 1a (AVPR1a), OXT receptor (OXTR), and protein kinase C isoform ß (PKCß), owing to the deactivated gene transcription, respectively. The deactivated AVPR1a, OXTR, and PKCB gene transcription were respectively linked with an increased DNA methylation within the gene promoter. CONCLUSIONS: To the best of our knowledge, this study first revealed that a hyper-methylation in gene promoter, leading to relatively reduced patterns of AVPR1a, OXTR, and PKCB expressions, which was responsible for the decreased sensitivity to AVP and OXT in the umbilical vein under conditions of pre-eclampsia. The data offered new and important information for further understanding the pathological features caused by pre-eclampsia in the fetal vascular system, as well as roles of epigenetic-mediated gene expression in umbilical vascular dysfunction.

DNA methylation-reprogrammed oxytocin receptor underlies insensitivity to oxytocin in pre-eclamptic placental vasculature.

Pre-eclampsia is associated with inadequate placental blood flow and placental ischaemia. Placental vascular tone is essential for maintaining adequate placental blood flow. Oxytocin is increased in placental system at late pregnancy and onset of labour, and presented strongly concentration-dependent contractions in placental vascular, suggesting that oxytocin could be involved in regulating placental vascular tone and circulation. However, information about the reactivity of oxytocin in pre-eclamptic placental vasculature is limited. This study used a large number of human placentas to reveal the pathophysiological changes and its underlying mechanisms of oxytocin-induced vasoconstrictions in placental vessels under pre-eclamptic condition. Present study found that oxytocin-induced contractions were significantly decreased in human pre-eclamptic placental vasculature, associated with a deactivated transcription of oxytocin receptor gene. The deactivated oxytocin receptor gene transcription was ascribed to a relatively higher DNA methylation status of CpG islands in oxytocin receptor gene promoter. This study was first to reveal that a hyper-methylation of CpG islands in oxytocin receptor gene promoter, leading to a relatively low pattern of oxytocin receptor expression, was responsible for the decreased sensitivity of oxytocin in pre-eclamptic placental vessels.

Magnesium Sulfate-Mediated Vascular Relaxation and Calcium Channel Activity in Placental Vessels Different From Nonplacental Vessels.

BACKGROUND: Magnesium sulfate (MgSO4) has been used as a common therapy for preeclampsia and eclampsia for many years. MgSO4 decreases peripheral vascular resistance so as to reduce maternal blood pressure. Whether placental blood vessels react to MgSO4 in the same patterns as that in maternal vessels is largely unknown. METHODS AND RESULTS: This study compared placental vessels (PV) versus nonplacental vessels (non-PV) in human and animal models. MgSO4-caused vascular dilation was significantly weaker in PV than that in non-PV. Prostaglandin I2 synthetase affected MgSO4-mediated vasodilatation in PV, not in umbilical vessels, while cyclooxygenase did not influence MgSO4-induced relaxation in both PV and non-PV. Mg2+-caused vasodilatation was mainly through calcium channels. In PV, calcium channel activities were significantly weaker in PV than that in non-PV. Relative mRNA expression of CACNA1D, CACNB2, and CACNB3 was significantly higher in PV than those in umbilical vessels, despite the fact that the expression of CACNA1F was less in PV. The contractile phenotype of smooth muscle cell marker (CALD1) was less and the synthetic phenotype (MYH10) was more in PV than that in UV. CONCLUSIONS: These results demonstrated that PV were characterized by much weaker responses to MgSO4 compared with nonplacental vessels. The difference was related to weaker calcium channel activity and minor contractile phenotype smooth muscle cells in PV, providing important information for further understanding treatments with MgSO4 in preeclampsia.

Impact of prenatal hypoxia on fetal bone growth and osteoporosis in ovariectomized offspring rats.

Prenatal hypoxia causes intrauterine growth retardation. It is unclear whether/how hypoxia affects the bone in fetal and offspring life. This study showed that prenatal hypoxia retarded fetal skeletal growth in rats, inhibited extracellular matrix (ECM) synthesis and down-regulated of insulin-like growth factor 1 (IGF1) signaling in fetal growth plate chondrocytes in vivo and in vitro. In addition, ovariectomized (OVX) was used for study of postmenopausal osteoporosis. Compared with the control, OVX offspring in prenatal hypoxic group showed an enhanced osteoporosis in the femurs, associated with reduced proteoglycan and IGF1 signaling. The results indicated prenatal hypoxia not only delayed fetal skeletal growth, but also increased OVX-induced osteoporosis in the elder offspring probably through down-regulated IGF1 signaling and inhibition of ECM synthesis, providing important information of prenatal hypoxia on functional and molecular bone growth and metabolism in fetal and offspring.

Synergetic Effects of Prenatal and Postnatal High Sucrose Intake on Glucose Tolerance and Hepatic Insulin Resistance in Rat Offspring.

SCOPE: High sucrose intake during pregnancy is linked to type 2 diabetes mellitus and altered insulin resistance. METHODS AND RESULTS: This study attempts to ascertain whether prenatal high sucrose intake (20% sucrose) alleviates the detrimental effects of high postnatal sugar consumption in the offspring, and the molecular mechanisms are investigated using a rat model. High prenatal sucrose exposure increases the body weight of the offspring at 1-3 weeks of age. Exposure to both prenatal and postnatal high sucrose increases glucose tolerance in the 4-month-old adult offspring compared with offspring receiving other treatments. Postnatal high sucrose exposure suppresses food intake but increases the total daily caloric and fluid intake. Both fasting blood glucose and plasma triglyceride levels are increased, but the fasting insulin level is unaffected. Prenatal high sucrose intake enlarges pancreatic islet area; however, prenatal-plus-postnatal high sucrose exposure induces smaller pancreatic islets. IRS-1(S612) protein phosphorylation is significantly increased, and the GSK-3ß (S9) phosphorylation level is reduced. CONCLUSION: Both prenatal and prenatal-plus-postnatal high sucrose exposure substantially affect biological functions related to insulin homeostasis. IRS-1(S612) protein phosphorylation appears to be a part of the molecular mechanism underlying these effects. These results add to the understanding of how high sucrose intake contributes to insulin resistance and diabetes pathogenesis and how postnatal nutrition and lifestyle may mitigate detrimental prenatal exposures.

Association between B7-H1 and cervical cancer: B7-H1 impairs the immune response in human cervical cancer cells.

The aim of the present study was to determine the preliminary mechanism of action of B7 homolog 1 (B7-H1) and investigate the association between B7-H1 and cervical cancer. The expression of B7 family proteins was measured in cervical cancer cells. Cervical cancer cells were co-cultured with T lymphocytes. An ELISA assay was subsequently conducted to analyze cytokine concentrations in the supernatants of the cultured T cells in cervical cancer cells and B7-H1 downregulated cells. Levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α mRNA in mice injected with cervical cancer cells or B7-H1 downregulated cells were measured by reverse transcription-quantitative polymerase chain reaction. It was determined that cervical cancer cells express high levels of B7-H1, whereas the normal cervical epithelium does not express B7-H1. When co-cultured with T lymphocytes, cervical cancer cells were involved in the inhibition of lymphocyte activation. When B7-H1 was downregulated using a lentivirus, the proliferation ability did not change compared with cervical cancer cells, whereas the soluble factors secreted by T cells differed between cervical cancer cells and B7-H1 downregulated cells. In an animal model, injected B7-H1 downregulated cervical cancer cells elicited a more intense immune response, whereas cervical cancer cells had the wild immune response. Therefore, the results of the present study demonstrate that B7-H1 mediates the low immunogenicity of cervical cancer and is not attacked by the immune system.

New conception for the development of hypertension in preeclampsia.

Placental vascular dysfunction was suggested to be critical for placental ischemia-initiated hypertension in preeclampsia, although the contributions of endothelium involved are unclear. The present study found, unlike non-placental vessels, acetylcholine showed no vasodilatation effect on placental vessels, indicating that endothelial-derived nitric oxide (NO) was extremely weak in placental vessels. Placental vascular responses to exogenous NO from sodium nitroprusside (SNP) were significantly different from non-placental vessels. These results were further confirmed in sheep, and rat vessels. In preeclamptic placental vessels, acetylcholine also showed no vasodilatation effects, while vascular responses to SNP were suppressed, associated with impaired cGMP/sGC pathway in vascular smooth muscle cells (VSMCs). The current theory on placental ischemia-initiated hypertension in preeclampsia focused on changes in placental vascular functions, including endothelial dysfunction. This study found the placental endothelium contributed very poorly to vasodilatation, and altered vascular functions in preeclampsia mainly occurred in VSMCs instead of endothelial cells. The findings contribute importantly to understanding the special feature of placental vascular functions and its pathophysiological changes in the development of hypertension in preeclampsia.

Exogenous melatonin reduced blood pressure in late-term ovine fetus via MT1/MT2 receptor pathways.

Melatonin is involved in the regulation of blood pressure through the receptor dependent or independent route. However, the effect of melatonin on fetal blood pressure is unknown. This study investigated the effect of melatonin on blood pressure of the late-term ovine fetus in utero. Melatonin and/or antagonists were intravenously administered into the fetuses. Mean arterial pressure and heart rate were recorded. Fetal blood samples were analyzed for biochemical parameters and hormones, including cortisol, angiotensin I, angiotensin II, aldosterone, atrial natriuretic peptide, corticotrophin-releasing hormone, adrenocorticotropic hormone, and endothelin. Fetal blood pressure was decreased following administration of melatonin, whereas it was increased following administration of luzindole, but not prazosin. Plasma level of endothelin was decreased by melatonin, which was blocked by luzindole. Our study suggested that melatonin reduced fetal blood pressure via MT1/MT2 receptors and possibly involving release of endothelin.

Disrupting the circadian photo-period alters the release of follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol in maternal and fetal sheep.

Although a large number of studies show that photo-period disruption potentially affects hormone secretion in mammals, information about the effects of circadian photo-period disruption during pregnancy on fetal blood reproductive hormone levels is scarce. This study used ewes and their fetuses to determine the effects of circadian photo-period disruption (deprivation of darkness) on follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone in maternal and fetal circulation at late gestation. Pregnant ewes (gestational age: 135 ± 3 days) were randomly placed into control and dark deprivation groups. The control (N = 5) and dark deprivation (N = 5) groups were exposed to a fixed 12 h light/12 h dark cycle and a 24 h constant light cycle, respectively, for 2 days. Dark deprivation up-regulated follicle-stimulating hormone and estradiol levels and down-regulated progesterone levels in both maternal and fetal circulation, and up-regulated luteinizing hormone levels in fetal but not maternal circulation. These results provide new information about how circadian photo-period disruption during pregnancy could alter the release of certain reproductive hormones into fetal blood, which may influence the development of fetal organs in utero, as well as long-term health.

5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human.

Preeclampsia and gestational diabetes mellitus (GDM) are the most common clinical conditions in pregnancy that could result in adverse in utero environments. Fetal exposure to poor environments may raise the long-term risk of postnatal disorders, while epigenetic modifications could be involved. Recent research has implicated involvement of 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine, via oxidation by ten-eleven translocation (TET) enzymes, in DNA methylation-related plasticity. Here, we show that the TET2 expression and 5hmC abundance are significantly altered in the umbilical veins of GDM and preeclampsia. Genome-wide profiling of 5hmC revealed its specific reduction on intragenic regions from both GDM and preeclampsia compared to healthy controls. Gene Ontology analysis using loci bearing unique GDM- and preeclampsia-specific loss-of-5hmC indicated its impact on several critical biological pathways. Interestingly, the substantial alteration of 5hmC on several transposons and repetitive elements led to their differential expression. The alteration of TET expression, 5hmC levels and 5hmC-mediated transposon activity was further confirmed using established hypoxia cell culture model, which could be rescued by vitamin C, a known activator of TET proteins. Together, these results suggest that adverse pregnancy environments could influence 5hmC-mediated epigenetic profile and contribute to abnormal development of fetal vascular systems that may lead to postnatal diseases.

Progesterone suppressed vasoconstriction in human umbilical vein via reducing calcium entry.

The aim of this study was to evaluate the actions of progesterone on human umbilical vein (HUV) from normal pregnancies and the possible underlying mechanisms involved. HUV rings were suspended in organ baths and exposed to progesterone followed by phenylephrine (PE) or serotonin (5-HT). Progesterone suppressed PE- or 5-HT-induced vasoconstriction in HUV rings. The inhibitory effect induced by progesterone was not influenced by nitric oxide syntheses inhibitor, prostaglandins syntheses blocker, the integrity of endothelium, selective progesterone receptor or potassium channel antagonists. Further testing showed that progesterone and nifedipine (a blocker for L-type calcium channels) produced similar inhibitory effects on PE-, 5-HT-, Bay-k8644-, KCl-induced vasoconstriction in Krebs solution as well as CaCl2-induced vasoconstriction in Ca(2+)-free Krebs solution. But the inhibitory effect of mibefradil (mibe, a blocker for L-type (CaV1.2) and T-type calcium channels (CaV3.2)) on PE-, 5-HT-induced vasoconstriction was significantly greater than progesterone or nifedipine in Krebs solution. Furthermore, progesterone did not affect the vasoconstriction caused by PE, 5-HT, or caffeine in Ca(2+)-free Krebs solution. In addition, incubation HUV with progesterone did not change CaV1.2 and progesterone receptor (PR) expressions. The results gained demonstrated that progesterone could suppress multiple agonist-induced vasoconstrictions in HUV, mainly due to a reduction of calcium entry through L-type calcium channels, not endothelium-dependent vascular relaxation pathways, potassium channels, or Ca(2+) release from intracellular stores, providing new information important to further understanding the contribution of progesterone in the regulation of the placental-fetal circulation.