Medical journal of obstetrics and gynecology最新文献

Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.

GATA transcription factors are Zinc finger members which perform a variety of important functions within the 3-germ layers as well as in extra embryonic endoderm during embryonic development. Distinct roles for GATA transcription factors have previously been identified in hematopoietic, the cardiac vascular system, the central neural system, as well as respiratory and intestinal systems. However, the role of GATA transcription factors in trophoblast lineage and placental development is far more complete. This review focuses on the roles of GATA transcription factors during pregnancy: the establishment of trophoblast lineage, trophoectoderm maintenance, trophoblast differentiation and the pathogenesis of placenta-related diseases of pregnancy.

Objective: To investigate a role of Vitamin D in the pathogenesis of preeclampsia (PE), and to discern any potential benefits of Vitamin D supplementation on hypertension in the RUPP rat model of PE.

Study design: Blood and placentas from normal pregnancies (NP) and PE were collected following elective cesarean delivery without evidence of infection. Circulating Vitamin D was extracted by HPLC and measured via mass spectrometry. Media for placenta explants was supplemented with Vitamin D and exposed to hypoxic (1% O2) or normoxic (6% O2) conditions for 24 hours. ELISAs were performed on media and normalized to total protein to determine cytokine secretion. RUPP rats were supplemented with vitamin D by oral gavage, and blood pressure (MAP) and pup weights were measured in NP and RUPP rats with or without Vitamin D supplementation. Flow cytometry was used to evaluate CD4⁺ Tcells in control RUPP rats and RUPP rats treated with Vitamin D.

Results: Inflammatory cytokine secretion was higher (p<0.05) while the anti-inflammatory cytokine, IL-10, was significantly lower in the media of PE placentas compared to NP (p=0.005). Vitamin D supplementation decreased hypoxia stimulated pro-inflammatory cytokine secretion (p=0.003) in the media of PE placentas. Vitamin D decreased MAP and circulating CD4⁺ T cells in the RUPP rat model of PE (p<0.05).

Conclusion: Vitamin D supplementation may be useful in the treatment or prevention of hypertensive disorders in pregnancy.

Preeclampsia is characterized as new onset maternal hypertension and proteinuria after 20 weeks gestation. Studies suggest that endothelin (ET-1) is a regulator of vascular function in preeclampsia and plays a major role in mediating chronic reduction in uterine perfusion pressure (RUPP)-induced hypertension. We recently demonstrated a role for the autoimmune cytokine interleukin 17 (IL-17) in causing placental oxidative stress and hypertension during pregnancy. In this current study, we investigated the role of ET-1 as a potential mechanism by which T_H17 cells and IL-17 mediate hypertension in preeclampsia. While IL-17 infusion into normal pregnant rats increased blood pressure in a dose-responsive manner (98+/-2 mmHg in NP (n=20) to 105+/-3 mmHg in IL-17 (50pg/day, n=20) to 120+/-4 mmHg in IL-17 (100pg/day, n=10) to 123+/-3 mmHg in IL-17 (150 pg/day, n=7), it decreased local endothelin in placentas (NP (n=10) 7.5±0.3; IL-17 (100 pg/day, n=5) 6.4±0.2; IL-17 (150 pg/day, n=12) 4.5+1.5) and renal cortices (NP (n=8) 7.9 + 0.4; IL-17 (100 pg/day, n=6) 7.1±0.4; IL-17 (150 pg/day, n=4) 1.6 +0.7 during pregnancy. In addition, increasing IL-17 directly reduced secretion of ET-1 by human umbilical venous endothelial cells (HUVECs). HUVEC ET-1 secretion decreased from that seen in serum free media 42.7±7.7 pg/ml to 36.2 ± 5.9 pg/ml at 10 pg IL-17 to 31.3 ± 5.1 pg/ml at 10 μg IL-17. Our observations suggest that IL-17 negatively regulates the ET-1 pathway in local tissues and cultured endothelial cells and that the ET-1 pathway is not a mechanism by which IL-17 causes hypertension during pregnancy.