ABSTRACT
Vasohibin-1 (VASH1) and vasohibin-2 (VASH2), the 2 members of the vasohibin family, have been identified as novel regulators of angiogenesis. VASH1 ceases angiogenesis, whereas VASH2 stimulates sprouting. Here we characterized their functional role in the placenta. Immunohistochemical analysis of human placental tissue clarified their distinctive localization; VASH1 in endothelial cells and VASH2 in trophoblasts. We then used a mouse model to explore their function. Wild-type, Vash1((-/-)), and Vash2((-/-)) mice on a C57BL6 background were used in their first pregnancy. As expected, the fetal vascular area was increased in the Vash1((-/-)) mice, whereas it was decreased in the Vash2((-/-)) mice relative to wild-type. In addition, we noticed that the Vash2((-/-)) mice at 18.5dpc displayed thinner villi of the labyrinth and larger maternal lacunae. Careful observation by an electron microscopy revealed that the syncytiotrophoblast formation was defective in the Vash2((-/-)) mice. To test the possible involvement of VASH2 in the syncytiotrophoblast formation, we examined the fusion of BeWo cells, a human trophoblastoid choriocarcinoma cell line. The forskolin treatment induced the fusion of BeWo cells, and the knockdown of VASH2 expression significantly inhibited this cell fusion. Conversely, the overexpression of VASH2 by the infection with adenovirus vector encoding human VASH2 gene significantly increased the fusion of BeWo cells. Glial cell missing-1 and endogenous retrovirus envelope glycoprotein Syncytin 1 and Syncytin 2 are known to be involved in the fusion of trophoblasts. However, VASH2 did not alter their expression in BeWo cells. These results indicate that VASH1 and VASH2 showed distinctive localization and opposing function on the fetoplacental vascularization. Moreover, our study shows for the first time that VASH2 expressed in trophoblasts is involved in the regulation of cell fusion for syncytiotrophoblast formation.
Subject(s)
Angiogenic Proteins/genetics , Cell Cycle Proteins/genetics , Neovascularization, Physiologic , Trophoblasts/metabolism , Adenoviridae/genetics , Adult , Angiogenic Proteins/metabolism , Animals , Cell Cycle Proteins/metabolism , Cell Fusion , Cell Line, Tumor , Colforsin/pharmacology , DNA-Binding Proteins , Female , Gene Expression Regulation , Gene Products, env/genetics , Gene Products, env/metabolism , Genetic Vectors , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Pregnancy , Pregnancy Proteins/genetics , Pregnancy Proteins/metabolism , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Trophoblasts/cytology , Trophoblasts/drug effectsABSTRACT
OBJECTIVE: To investigate the efficacy of recombinant human soluble thrombomodulin (rTM) in disseminated intravascular coagulation (DIC) associated with severe postpartum hemorrhage (PPH). PATIENTS AND METHODS: We conducted a retrospective review of 36 patients with severe PPH complicated by DIC admitted to a single tertiary center. The first 26 patients were treated without rTM (control group), and the next 10 consecutive patients were treated with rTM. Clinical parameters including bleeding symptoms and coagulation indices were evaluated. RESULTS: Baseline characteristics, total blood loss, and transfusion requirements were similar between the 2 groups. On day 2, there was a significant difference between the 2 groups in the decrease in d-dimer level from baseline. The incidence of bleeding symptoms was decreased in the rTM group compared with the control group. No adverse events were observed in the rTM group. CONCLUSION: Recombinant human thrombomodulin may be an effective adjunctive therapy in the management of DIC related to PPH.
Subject(s)
Disseminated Intravascular Coagulation/drug therapy , Postpartum Hemorrhage/drug therapy , Thrombomodulin/therapeutic use , Adult , Disseminated Intravascular Coagulation/blood , Female , Humans , Postpartum Hemorrhage/blood , Pregnancy , Recombinant Proteins/therapeutic use , Retrospective StudiesABSTRACT
Maternal undernutrition during pregnancy is a risk factor for cerebrovascular and cardiovascular diseases in adulthood. Hypoxia-inducible factor 1 alpha (HIF1α) plays an essential role in cellular hypoxic responses, and its increased expression is associated with cerebrovascular and cardiovascular diseases. However, it is not known whether maternal undernutrition influences HIF1α expression in the fetal brain. We therefore analyzed the expression levels of HIF1α and its downstream genes in the fetal brain (day 17.5 of gestation, 1-2 days before birth). Maternal undernutrition did not noticeably affect the fetal body and brain weights. Both HIF1α mRNA and protein levels were increased in the brain under maternal undernutrition, despite the absence of hypoxia, as judged by the staining profile with hypoxyprobe-1 that identifies hypoxic cells. Importantly, maternal undernutrition caused the accumulation of HIF1α protein in oligodendrocyte precursor cells at the subventricular zone, a site of neurogenesis in the fetal brain. Maternal undernutrition also increased the mRNA level of mammalian target of rapamycin (mTOR), which could increase the level of HIF1α protein under normoxia. Furthermore, microarray analysis revealed that expression levels of mRNAs for 10 HIF1α downstream targets, including enolase 1 and hexokinase 1, were increased in the fetal brain under maternal undernutrition. Thus, the biochemical consequence of maternal undernutrition is similar to that of mild hypoxia. In conclusion, maternal undernutrition induces the expression of HIF1α in oligodendrocyte precursor cells at the subventricular zone, and it also induces the expression of hypoxia-related genes in the fetal brain probably via activation of the mTOR pathway.
Subject(s)
Fetus/metabolism , Gene Expression Regulation, Developmental/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia/metabolism , Malnutrition/physiopathology , Maternal Nutritional Physiological Phenomena/physiology , Animals , DNA Primers/genetics , Female , Hexokinase/metabolism , Hypoxia/genetics , Immunohistochemistry , Maternal Nutritional Physiological Phenomena/genetics , Mice , Mice, Inbred C57BL , Microarray Analysis , Phosphopyruvate Hydratase/metabolism , Pregnancy , Real-Time Polymerase Chain Reaction , Statistics, Nonparametric , TOR Serine-Threonine Kinases/metabolismABSTRACT
Maternal undernutrition during pregnancy is a risk factor that impairs fetal growth and causes cardiovascular diseases. However, the underlying mechanism is still unknown. In this study, we evaluated the effect of maternal undernutrition on the expression levels of transcription factors in the fetal heart. Female mice were given low protein or regular food from 2 weeks before mating and during their pregnancy. The fetal hearts were collected on day 17.5 of gestation, about 1-2 days before birth. Maternal undernutrition resulted in a significant increase in the relative heart weight (heart weight/body weight) in female fetuses, but not in male fetuses. Microarray analysis revealed that expression levels of mRNAs for 133 transcription factors were changed in the fetal heart under maternal undernutrition. Among them, we focused on hypoxia-inducible factor 1 alpha (HIF1α) that is involved in the pathogenesis of cardiovascular diseases on adulthood. Quantitative real-time PCR analysis showed that the expression level of HIF1α mRNA was increased about 1.3-fold in male fetal heart under maternal undernutrition, but remained unchanged in female heart. Moreover, maternal undernutrition increased the mRNA level of prolyl hydroxylase 1 (PHD1), which contributes to degradation of HIF1α, in male heart but not in female heart. Immunohistochemical analysis showed the accumulation of HIF1α protein in the fetal heart of both sexes under maternal undernutrition, without the induction of HIF1α mRNA expression in female heart. These results suggest that maternal undernutrition may induce HIF1α expression in the fetal heart through the distinct mechanisms depending on the sex.