Cytochrome c oxidase IV isoform 1 (COX4-1) regulates the proliferation, migration and invasion of trophoblast cells via modulating mitochondrial function.

INTRODUCTION: Spontaneous miscarriage is a common complication of early pregnancy. Previous studies have shown that mitochondrial function plays an important role in establishment of a successful pregnancy. Cytochrome c oxidase subunit 4 isoform 1 (COX4I1), a component of electron transport chain complex Ⅳ, is required for coupling the rate of ATP production to energetic requirements. However, there is very limited research on its role in trophoblast biology and how its dysfunction may contribute to spontaneous miscarriage. METHODS: Placental villi (7-10 weeks gestational age) collected from either induced termination of pregnancy or after spontaneous miscarriage were examined for expression of COX4I1. COX4I1 was knocked down by siRNA transfection of primary isolates of EVT cells. Real-time cell analysis (RTCA) and 5-Ethynyl-2'-deoxyuridine (EdU) were used to detect changes in proliferation ability after COX4I1 knockdown of EVT cells. Migration and invasion indices were determined by RTCA. Mitochondrial morphology was observed via MitoTracker staining. Oxidative phosphorylation, ATP production, and glycolysis in COX4I1-deficient cells and controls were assessed by a cellular energy metabolism analyzer (Seahorse). RESULTS: In placental villous tissue, COX4I1 expression was significantly decreased in the spontaneous miscarriage group. Knockdown of COX4I1 inhibited EVT cell proliferation, increased the migration and invasion ability and mitochondrial fusion of EVT cells. Mitochondrial respiration and glycolysis were impaired in COX4I1-deficient EVT cells. Knockdown of MMP1 could rescue the increased migration and invasion induced by COX4I1 silencing. DISCUSSION: Low expression of COX4I1 leads to mitochondrial dysfunction in EVT, resulting in altered trophoblast function, and ultimately to pregnancy loss.

Interleukin-1 beta signals through the ERK signalling pathway to modulate human placental trophoblast migration and invasion in the first trimester of pregnancy.

INTRODUCTION: Interleukin-1 beta (IL-1ß) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1ß in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration. METHODS: First trimester placenta and decidua were collected to study the expression levels of IL-1ß and its receptors by immunohistochemical staining. Primary isolates of first trimester EVT or the HTR-8/SVneo trophoblast like cell line were used to assess migration and invasion. Matrix metalloproteinase levels were assessed by gelatin zymography and ELISA. The phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. Differentially expressed proteins in cells was detected and verified by Western Blot. RESULTS: IL-1ß, its receptors and antagonist are expressed in first trimester placenta and decidua, exogenous IL-1ß stimulates trophoblast cell outgrowth, migration and invasion through the ERK signaling pathway. IL-1ß was significantly increased in the placenta at 6-7 weeks gestation compared with 8-9 weeks gestation (P < 0.0001). Transwell and RTCA assays indicated that IL-1ß stimulates the invasion and migration of EVT. In addition, IL-1ß promoted the phosphorylation of ERK 1/2. It also promoted the expression of MMP2 and MMP9 in EVT as demonstrated by gelatin zymography assay and enzyme linked immunosorbent assay. DISCUSSION: This study demonstrated IL-1ß expression in placenta and decidua, and that it regulates EVT invasion and migration.

Uterine Commensal Peptostreptococcus Species Contribute to IDO1 Induction in Endometrial Cancer via Indoleacrylic Acid.

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

Sonographic Findings of Vascular Signals for Retained Products of Conception in Women Following First-Trimester Termination of Pregnancy.

OBJECTIVES: To evaluate the occurrence of retained products of conception (RPOC) after termination of pregnancy in the first trimester and to assess the vascular signals with transvaginal ultrasonography (TVUS) examination in the detection of retained products. METHODS: A retrospective cohort study was performed using TVUS examination in patients following termination of pregnancy. In cases of RPOC, 3 scales of vascular signal were identified: type 1, no or small amount, spot flow signals; type 2, medium amount, strip-like flow signals; type 3, rich amount, circumferential-like flow signals. The correlation between vascular signals and placenta accreta spectrum (PAS) staging was proposed by sonography and histopathology findings. RESULTS: The 3 vascular patterns were differently distributed within non-RPOC as well as RPOC patients with and without PAS: type 1 vascular signal detection rates of non-RPOC and RPOC were 97.8% (262/268) and 28.1% (18/64), respectively. Of 64 cases of RPOC, 48.4% (31/64) of the patients had type 2 vascular signals. Vascular signals were enhanced in RPOC with PAS patients whose diagnosis was confirmed by histopathology. CONCLUSIONS: The vascularity (amount of flow), vascular pattern (spot, strip- or circumferential-like flow), and the flow penetrating myometrium were significant findings for distinguishing concomitant RPOC with and without PAS. Additionally, RPOC may contribute to PAS progression, or PAS and RPOC in coordination strengthen the observed vascular signals.

Unraveling the mysteries of spiral artery remodeling.

Spiral artery remodeling is the process by which the uterine vessels become large bore low resistance conduits, allowing delivery of high volumes of maternal blood to the placenta to nourish the developing fetus. Failure of this process is associated with the pathophysiology of most of the major obstetric complications, including late miscarriage, fetal growth restriction and pre-eclampsia. However, the point at which remodeling 'fails' in these pathological pregnancies is not yet clear. Spiral artery remodeling has predominantly been described in terms of its morphological features, however we are starting to understand more about the cellular and molecular triggers of the different aspects of this process. This review will discuss the current state of knowledge of spiral artery remodeling, in particular the processes involved in loss of the vascular smooth muscle cells, and consider where in the process defects would lead to a pathological pregnancy.

Extravillous trophoblast cell-derived exosomes induce vascular smooth muscle cell apoptosis via a mechanism associated with miR-143-3p.

The remodeling of uterine spiral arteries is a complex process requiring the dynamic action of various cell types. During early pregnancy, extravillous trophoblast (EVT) cells differentiate and invade the vascular wall, replacing the vascular smooth muscle cells (VSMCs). Several in vitro studies have shown that EVT cells play an important role in promoting VSMC apoptosis, however, the mechanism underlying this process is not fully understood. In this study, we demonstrated that EVT-conditioned media and EVT-derived exosomes could induce VSMC apoptosis. Through data mining and experimental verification, it was demonstrated that the EVT exosome miR-143-3p induced VSMC apoptosis in both VSMCs and a chorionic plate artery (CPA) model. Furthermore, FAS ligand was also expressed on the EVT exosomes and may play a co-ordinated role in apoptosis induction. These data clearly demonstrated that VSMC apoptosis is mediated by EVT-derived exosomes and their cargo of miR-143-3p as well as their cell surface presentation of FASL. This finding increases our understanding of the molecular mechanisms underlying the regulation of VSMC apoptosis during spiral artery remodeling.

Knockdown of heat shock protein family D member 1 (HSPD1) promotes proliferation and migration of ovarian cancer cells via disrupting the stability of mitochondrial 3-oxoacyl-ACP synthase (OXSM).

BACKGROUND: Heat shock protein 60 (HSP60) is essential for the folding and assembly of newly imported proteins to the mitochondria. HSP60 is overexpressed in most types of cancer, but its association with ovarian cancer is still in dispute. SKOV3 and OVCAR3 were used as experimental models after comparing the expression level of mitochondrial HSP60 in a normal human ovarian epithelial cell line and four ovarian cancer cell lines. RESULTS: Low HSPD1 (Heat Shock Protein Family D (HSP60) Member 1) expression was associated with unfavorable prognosis in ovarian cancer patients. Knockdown of HSPD1 significantly promoted the proliferation and migration of ovarian cancer cells. The differentially expressed proteins after HSPD1 knockdown were enriched in the lipoic acid (LA) biosynthesis and metabolism pathway, in which mitochondrial 3-oxoacyl-ACP synthase (OXSM) was the most downregulated protein and responsible for lipoic acid synthesis. HSP60 interacted with OXSM and overexpression of OXSM or LA treatment could reverse proliferation promotion mediated by HSPD1 knockdown. CONCLUSIONS: HSP60 interacted with OXSM and maintained its stability. Knockdown of HSPD1 could promote the proliferation and migration of SKOV3 and OVCAR3 via lowering the protein level of OXSM and LA synthesis.

Incidence and risk factors of hearing loss in patients with Turner Syndrome.

Background: Hearing loss (HL) is one of the main medical complications for Turner Syndrome (TS) patients, with an earlier presentation and higher incidence than normal women. However, the etiology of HL in TS is unclear. The aim of this study was to investigate the hearing status of TS patients in China and the influencing factors, so as to provide a theoretical basis for early intervention treatment for TS patients with HL. Methods: In total 46 female patients aged 14-32 diagnosed with TS received tympanic membrane and audiological examinations, including pure tone audiometry and tympanometry. In addition, the effects of karyotype, sex hormone levels, thyroid function, insulin, blood lipids, bone mineral density, age and other factors on hearing levels were analyzed, and the possible risk factors associated with HL in TS patients were explored. Results: In 9 patients (19.6%) had HL, including 1 (2.2%) with mild conductive hearing loss, 5 (10.9%) with mild sensorineural hearing loss, 3 (6.5%) with moderate sensorineural hearing loss. TS is often associated with age-related mid-frequency and high-frequency HL, and the incidence of HL increases with age. Compared with other karyotypes, patients with 45, X haplotype have an increased risk of mid-frequency HL. Conclusions: Therefore, karyotype may be a predictor of hearing problems in TS.

Tumor-Derived Oxidative Stress Triggers Ovarian Follicle Loss in Breast Cancer.

Breast cancer is a common indication for ovarian cryopreservation. However, whether the grafting ovarian tissue meets functional requirements, as well as the need for additional interventions, remains unclear. The current study demonstrates abnormal serum hormones in breast cancer in humans and breast cancer cell line-derived tumor-bearing mice, and for the first time shows tumor-induced loss of primordial and growing follicles, and the number of follicles being lost to either growth or atresia. A gene signature of tumor-bearing mice demonstrates the disturbed regulatory network of steroidogenesis, which links to mitochondria dysfunction in oocytes and granulosa cells via the phosphatidylinositol 3-kinase signaling pathway. Notably, increased reactive oxygen species were identified in serum and ovarian tissues in tumor-bearing mice. Furthermore, supplementation with vitamin C promoted follicular quiescence, repairing tumor-induced follicle loss via inactivation of the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, indicating the potential of antioxidants as a fertility therapy to achieve higher numbers of healthy follicles ready for ovarian cryopreservation.

Hypoxia-Driven TGFß Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα.

Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-ß1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl2 exposure and TGF-ß driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-ß1 and CoCl2 treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-ß1 treatment significantly reduced the MCF7 SP cells, CoCl2 exposure led to a significant increase. Single cell analysis revealed that CoCl2 exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl2 exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.

Ezrin accelerates breast cancer liver metastasis through promoting furin-like convertase-mediated cleavage of Notch1.

BACKGROUND: Ezrin, known as a crosslinker between the plasma membrane and actin cytoskeleton, is closely associated with breast cancer (BC) progression. Here, we explored a novel role of ezrin in breast cancer liver metastasis (BCLM). METHODS: The clinical relevance of ezrin was evaluated using in silico tools and confirmed in BC specimens. The effect of ezrin on proliferation, migration and invasion was examined in vitro and in vivo using murine primary liver-metastatic breast cancer cells (mLM). The molecular mechanism involved in ezrin-mediated activation of the Notch1 signaling pathway was elucidated using in vitro models. RESULTS: Data-mining demonstrated that ezrin mRNA and protein expression is up-regulated in breast cancer cohorts and has prognostic significance. Ezrin overexpression promotes cell proliferation, migration and invasion in vitro and in vivo. Hairy and enhancer of split-1 (Hes1) is one of the most significantly enriched candidates of differentially expressed genes in ezrin overexpression and control mLM cells. Ezrin can positively regulate Hes1 mRNA and protein expression, and their coexpression was associated with poor prognosis in BC patients. Ezrin promoted BC cell proliferation in a Hes1-dependent manner without directly interacting with Hes1. The functional link between ezrin and Hes1 is dependent on Notch1 activation through promotion of furin-like convertase cleavage. CONCLUSION: Our results demonstrated that ezrin drives BCLM through activation of the Notch signaling pathway via furin-like convertase. These findings provide a better understanding of the mechanism of ezrin in breast cancer progression, with the goal of discovering a novel target for the treatment of BCLM in the future.

SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway.

Preeclampsia (PE) is the leading cause of maternal and fetal morbidity or mortality but lacks reliable methods for early diagnosis. In a previous study, serum SERPINA5 levels were higher in women with PE before the clinical manifestation of the disease. This study aimed to evaluate the efficacy of SERPINA5 in predicting PE and investigate its role in trophoblast cell biology. A multicenter, 2-stage observational case-control study was performed to develop and validate an early predictive PE model based on SERPINA5, maternal characteristics, and inflammatory factors. To further understand the relationship between SERPINA5 and PE, SERPINA5 was overexpressed or knocked down in extravillous trophoblast cells (EVT) and a pregnant rat model. After development and initial validation, a model that combined SERPINA5 and inflammatory factors had a high predictive ability for PE before 20 weeks gestation with an AUC of 0.90 (95% CI 0.83-0.96). It also demonstrated that SERPINA5 inhibited primary EVT cell invasion by disrupting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) pathway, in turn, is involved in the development of PE. In vivo experiments also proved that overexpression of SERPINA5 induced a PE-like syndrome (hypertension and proteinuria) in pregnant rats. Therefore, serum SERPINA5 is a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on the uPA/uPAR system prior to the clinical manifestation of PE.

Extravillous trophoblast invasion and decidualization in cesarean scar pregnancies.

INTRODUCTION: The increasing cesarean section rate has led to an increase in the number of subsequent pregnancies resulting in a cesarean scar pregnancy. There appears to be preferential attachment of the blastocyst to the scar site, which may be associated with defective decidua in that region, resulting in abnormal implantation, which can in turn negatively affect the success of the pregnancy. The aim of the current study was to evaluate the extravillous trophoblast, decidua, and myometrium in scar and adjacent non-scar regions of the implantation site of a cesarean scar pregnancy. MATERIAL AND METHODS: Samples containing a gestational mass were obtained by laparoscopic excision from patients with a cesarean scar pregnancy at 6-11 weeks of gestation as diagnosed by transvaginal or transabdominal ultrasound (n = 8 type II cesarean scar pregnancy). Cesarean scar pregnancy tissues were separated into scar and non-scar regions, and the scar regions were sub-separated into non-implantation and implantation sites. Serial sections were histologically examined after hematoxylin and eosin, Masson's trichrome and immunochemical staining, and changes in the myometrium, extravillous trophoblast, and decidua were evaluated. RESULTS: In cesarean scar pregnancy, compared with scars not in the implantation site, scars in the implantation site displayed increased fibrosis, and had disrupted myometrium, which was related to varying patterns of E-cadherin expression as a response to extravillous trophoblast invasion. In addition, local decidua was found at the non-scar implantation sites, with multinucleated trophoblast giant cell accumulation and shallow invasion. These features were not evident in the scar implantation sites. CONCLUSIONS: This study emphasizes that the decidua drives multinucleated trophoblast giant cell differentiation, limiting the degree of invasion. Better characterization of this differentiation process may be helpful for better management and avoidance of the consequences of cesarean scar pregnancy.

Role of osteopontin (OPN) in uterine spiral artery remodeling.

Uterine spiral artery (SpA) remodeling is critical for a successful pregnancy. The deficiency of SpA remodeling seriously affects the blood perfusion of the placenta, impacting the nutritional supply to the fetus and therefore fetal growth and development, which is one of the pathological causes of pregnancy related diseases. This process involves the interaction between all cells and related factors at the maternal-fetal interface, especially extravillous trophoblast cells (EVT), vascular smooth muscle cells (VSMCs) and decidual immune cells. Osteopontin (OPN), as a glycosylated protein, is widely localized in the extracellular matrix and participates in a variety of cellular activities such as migration, adhesion, differentiation and survival. OPN plays an important role in placental development, uterine decidualization and pregnancy success. This study focuses on the role of OPN in uterine spiral artery remodeling and its related molecular mechanism.

Platelet-derived growth factor BB is reduced in endometrial endothelial cells of women with abnormal uterine bleeding-endometrial disorder.

RESEARCH QUESTION: What is the expression pattern of platelet-derived growth factor BB (PDGF-BB), and its receptors, across the menstrual cycle in healthy control women and those with abnormal uterine bleeding-endometrial disorder (AUB-E)? DESIGN: Immunohistochemical staining for PDGF-BB, platelet-derived growth factor receptor alpha (PDGFRα) and platelet-derived growth factor beta (PDGFRß) was performed in control and AUB-E endometrium from the proliferative, early, mid- and late secretory phases of the menstrual cycle (n = 5 each group). Control proliferative phase endometrium was cultured in PDGF-BB (0, 10 ng/ml) and vascular maturation assessed (n = 3). Endothelial cell to vascular smooth muscle cell (VSMC) association was assessed after treatment with PDGF-BB (0, 1, 10 ng/ml). Secretion of angiogenic growth factors by endothelial cells or VSMC was determined. RESULTS: Endothelial cell immunoreactivity for PDGF-BB was reduced in the mid and late secretory phases in AUB-E (P = 0.008). PDGFRα was also reduced in mid secretory phase endothelial cells, proliferative and early secretory phase glandular epithelium in AUB-E (P = 0.008). PDGFRß expression was not altered. Treatment of proliferative phase endometrium with PDGF-BB (10 ng/ml) reduced the percentage of vessels expressing contractile VSMC markers. PDGF-BB had no effect on angiogenic growth factor secretion by endothelial cells or VSMC in vitro and did not affect their association in an in-vitro endothelial cell-VSMC association assay. CONCLUSIONS: Reduced endothelial cell expression of PDGF-BB in the AUB-E endometrium may contribute to the reduced vascular maturation previously observed in these women.

Is there a place for Traditional Chinese Medicine (TCM) in the treatment of recurrent pregnancy loss?

Recurrent pregnancy loss (RPL) impacts a couple's quality of life, mental health and constitutes a large economic burden for care. Traditional Chinese Medicine (TCM) is an integrated systematic medical practice with wide clinical applications that has been predominantly used throughout Asian countries for over 2000 years. However, the efficacy of TCM in the treatment of RPL remains unclear due not only to a lack of experimental evidence, but also a lack of comprehensive summarized conclusions. Therefore, the current manuscript reviews recent relevant publications of the clinical use of TCM in RPL and illustrates its potential mechanisms. All publications (in both Chinese and English), especially randomized controlled trials (RCTs), on the use of TCM in RPL for the last ten years and research on its mechanisms were included. This review also describes our understanding of the problems and challenges in the modernization of TCM research.

SIRT1 regulates trophoblast senescence in premature placental aging in preeclampsia.

INTRODUCTION: Premature placental aging is implicated in a number of complications of pregnancy including preeclampsia. A placenta knockout mouse model has shown a relationship between SIRT1, aging and placental dysfunction. The role of SIRT1 in cellular senescence has been extensively studied in various cell types, but its role in trophoblast senescence is almost unknown. METHODS: Human placental samples were obtained from preeclampsia-affected women and healthy controls. The placental aging profiles were assessed by Doppler ultrasound, placental histopathology, and evaluation of senescence- and ECM-related markers. The SIRT1 expression pattern relevant to placental aging profiles was studied in premature aging placenta with preeclampsia (32-37 weeks gestation, n = 10) and healthy controls (37-40 weeks gestation, n = 10). Using cell culture, the effects of activation and knockdown of SIRT1 or its downstream target molecules in syncytialized BeWo cells were evaluated. RESULTS: SIRT1 was expressed by syncytiotrophoblast across normal gestation. In preeclamptic premature aging placentas, SIRT1 was significantly downregulated, while senescence- and extracellular matrix (ECM) -related protein levels were upregulated compared to controls. Immunohistochemistry showed these changes to be confined to syncytiotrophoblast. In vitro, SIRT1 activation in response to resveratrol (RSV) abrogated senescence in forskolin-induced syncytialization of BeWo cells via regulation of senescence- and ECM-related proteins, and filamentous actin (F-actin). These effects were restored by SIRT1 siRNA. DISCUSSION: The downregulation of SIRT1 may accelerate senescence of syncytiotrophoblast via targets contributing to regulation of the cell cycle, ECM production and cytoskeleton reorganization leading to premature placental aging observed in preeclampsia.

Contribution of vascular smooth muscle cell apoptosis to spiral artery remodeling in early human pregnancy.

Uterine spiral artery remodeling is one of the key maternal adaptations of pregnancy, allowing delivery of the large volumes of maternal blood required for both placental and fetal growth. Failure of this process is associated with obstetric complications including preeclampsia, fetal growth restriction and miscarriage. Spiral artery remodeling is characterized by loss of the musculoelastic wall which is replaced by fibrinoid and intramural extravillous trophoblast cells (EVT). In recent years attention has focused on the initial stages of spiral artery remodeling which include separation of the vascular smooth muscle cells (VSMCs) and their phenotypic switch to a more synthetic phenotype, facilitating their migration away from the vessel wall. However, less is known about the final fate of the VSMCs. In vitro studies suggested that EVT could induce VSMC apoptosis, though VSMC apoptosis is not seen within the wall of the spiral arteries undergoing remodeling. However, apoptotic VSMCs have been observed amongst those cells which had migrated away from the vessel wall. This review article gives a brief overview of the current state of knowledge of the processes involved in spiral artery remodeling, and then concentrates on the mechanisms involved in VSMC apoptosis, drawing on knowledge from other vascular beds.