DNA methylation landscape in pregnancy-induced hypertension: progress and challenges.

Gestational hypertension (PIH), especially pre-eclampsia (PE), is a common complication of pregnancy. This condition poses significant risks to the health of both the mother and the fetus. Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may play a role in initiating the earliest pathophysiology of PIH. This article describes the relationship between DNA methylation and placental trophoblast function, genes associated with the placental microenvironment, the placental vascular system, and maternal blood and vascular function, abnormalities of umbilical cord blood and vascular function in the onset and progression of PIH, as well as changes in DNA methylation in the progeny of PIH, in terms of maternal, fetal, and offspring. We also explore the latest research on DNA methylation-based early detection, diagnosis and potential therapeutic strategies for PIH. This will enable the field of DNA methylation research to continue to enhance our understanding of the epigenetic regulation of PIH genes and identify potential therapeutic targets.

HDAC1/2/3-mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism.

Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.

Current data and future perspectives on DNA methylation in ovarian cancer (Review).

Ovarian cancer (OC) represents the most prevalent malignancy of the female reproductive system. Its distinguishing features include a high aggressiveness, substantial morbidity and mortality, and a lack of apparent symptoms, which collectively pose significant challenges for early detection. Given that aberrant DNA methylation events leading to altered gene expression are characteristic of numerous tumor types, there has been extensive research into epigenetic mechanisms, particularly DNA methylation, in human cancers. In the context of OC, DNA methylation is often associated with the regulation of critical genes, such as BRCA1/2 and Ras­association domain family 1A. Methylation modifications within the promoter regions of these genes not only contribute to the pathogenesis of OC, but also induce medication resistance and influence the prognosis of patients with OC. As such, a more in­depth understanding of DNA methylation underpinning carcinogenesis could potentially facilitate the development of more effective therapeutic approaches for this intricate disease. The present review focuses on classical tumor suppressor genes, oncogenes, signaling pathways and associated microRNAs in an aim to elucidate the influence of DNA methylation on the development and progression of OC. The advantages and limitations of employing DNA methylation in the diagnosis, treatment and prevention of OC are also discussed. On the whole, the present literature review indicates that the DNA methylation of specific genes could potentially serve as a prognostic biomarker for OC and a therapeutic target for personalized treatment strategies. Further investigations in this field may yield more efficacious diagnostic and therapeutic alternatives for patients with OC.

DNA methylation-mediated 11ßHSD2 downregulation drives the increases in angiotensin-converting enzyme and angiotensin II within preeclamptic placentas.

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11ß-hydroxysteroid dehydrogenases (11ßHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11ßHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11ßHSD2 gene promoter and its expression, meanwhile, 11ßHSD2 expression was negatively correlated with cortisol and ACE levels. In vitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11ßHSD2 knockdown could enhance this activating effect. An in vivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11ßHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE.

GR/P300 Regulates MKP1 Signaling Pathway and Mediates Depression-like Behavior in Prenatally Stressed Offspring.

Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health.

Gestational Hypoxia Impaired Endothelial Nitric Oxide Synthesis Via miR-155-5p/NADPH Oxidase/Reactive Oxygen Species Axis in Male Offspring Vessels.

BACKGROUND: Nitric oxide (NO) is the most important vasodilator secreted by vascular endothelial cells, and its abnormal synthesis is involved in the development of cardiovascular disease. The prenatal period is a critical time for development and largely determines lifelong vascular health in offspring. Given the high incidence and severity of gestational hypoxia in mid-late pregnancy, it is urgent to further explore whether it affects the long-term synthesis of NO in offspring vascular endothelial cells. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. The thoracic aortas of fetal and adult male offspring were isolated for experiments. Gestational hypoxia significantly reduces the NO-dependent vasodilation mediated by acetylcholine in both the fetal and adult offspring thoracic aorta rings. Meanwhile, acetylcholine-induced NO synthesis is impaired in vascular endothelial cells from hypoxic offspring thoracic aortas. We demonstrate that gestational hypoxic offspring exhibit a reduced endothelial NO synthesis capacity, primarily due to increased expression of NADPH oxidase 2 and enhanced reactive oxygen species. Additionally, gestational hypoxic offspring show elevated levels of miR-155-5p in vascular endothelial cells, which is associated with increased expression of NADPH oxidase 2 and reactive oxygen species generation, as well as impaired NO synthesis. CONCLUSIONS: The present study is the first to demonstrate that gestational hypoxia impairs endothelial NO synthesis via the miR-155-5p/NADPH oxidase 2/reactive oxygen species axis in offspring vessels. These novel findings indicate that the detrimental effects of gestational hypoxia on fetal vascular function can persist into adulthood, providing new insights into the development of vascular diseases.

Calcium signals and potential therapy targets in ovarian cancer (Review).

Ovarian cancer (OC) is a deadly disease. The poor prognosis and high lethality of OC are attributed to its high degrees of aggressiveness, resistance to chemotherapy and recurrence rates. Calcium ion (Ca2+) signaling has received attention in recent years, as it appears to form an essential part of various aspects of cancer pathophysiology and is a potential therapeutic target for OC treatment. Disruption of normal Ca2+ signaling pathways can induce changes in cell cycle progression, apoptosis, proliferation and migration and invasion, leading to the development of the malignant phenotype of tumors. In the present review, the main roles of ion channel/receptor/pump­triggered Ca2+ signaling pathways located at the plasma membrane and organelle Ca2+ transport in OC are summarized. In addition, the potential of Ca2+ signaling as a novel target for the development of effective treatment strategies for OC was discussed. Furthering the understanding into the role of Ca2+ signaling in OC is expected to facilitated the identification of novel therapeutic targets and improved clinical outcomes for patients.

CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.

Prenatal dexamethasone exposure impaired vascular reactivity in adult male offspring cerebral arteries.

BACKGROUND: Cerebrovascular disease is one of the leading causes of death worldwide. Middle cerebral artery (MCA) is the largest and most complex of cerebral arteries. The prenatal period is a critical time for development, which largely determines lifelong health. Clinically, glucocorticoids (GCs) administration to accelerate preterm fetal lung maturation has become standard practice. Prenatal GCs administration increases cardiovascular risks in offspring, but little is known regarding the side effects on offspring MCA function. OBJECTIVE: We investigated the alterations of MCA reactivity following prenatal GCs administration in postnatal offspring. METHOD AND RESULTS: Pregnant Sprague-Dawley rats received synthetic GCs (dexamethasone, DEX) during the last week of pregnancy, and we examined vascular reactivity, cellular electrophysiology, and gene promoter epigenetic modifications in the male offspring MCA. Our results showed that prenatal DEX exposure increased the sensitivity of offspring MCA to Angiotensin II, which was resulted from the increased Cav1.2 (L-type Ca2+ channels subunit alpha1 C). Mechanistically, prenatal DEX exposure resulted in a transcriptionally active chromatin structure at the Cav1.2 gene promoter by altering histone modifications. This activation led to increased expression of vascular Cav1.2 gene, ultimately resulting in increased MCA contractility in offspring. CONCLUSION: The present study is the first to demonstrate that the adverse effects of prenatal GCs administration on cerebrovascular tone persist into adulthood, providing new insights into developmental origins of cerebrovascular disease.

Peripheral CD4+CD25hiCD127low regulatory T cells are increased in patients with gastrointestinal cancer.

BACKGROUND: Regulatory T cells (Tregs) play an important role in regulation of immune response and immunologic tolerance in cancer. Gastrointestinal cancer is still a leading cause of cancer-related death in the world. This study aimed to detect Tregs in patients with gastrointestinal cancer. METHODS: In this study, 45 gastric cancer patients, 50 colorectal cancer patients and 50 healthy controls were enrolled. Flow cytometry was used to detect CD4+CD25hiCD127low Tregs, CD4+CD25hi, and CD4+ cells in peripheral blood. Cytokine interleukin-10 (IL-10) and transforming growth factor-ß1 (TGF-ß1) in peripheral blood and in the supernatant of Tregs cultures were measured by enzyme linked immunosorbent assay. RESULTS: Compared with healthy controls, the levels of CD4+CD25hiCD127low Tregs and CD4+CD25hi cells increased significantly in patients with gastrointestinal cancer. Patients with gastrointestinal cancer also showed a significantly increased levels of IL-10 and TGF-ß1 in both peripheral blood and CD4+CD25hiCD127low Tregs culture medium. CONCLUSION: The present study firstly demonstrated that gastrointestinal patients have a compromised immune status where the CD4+CD25hiCD127low Tregs, as well as levels of IL-10 and TGF-ß1 are elevated. The data offered new information for understanding the immunological features of gastrointestinal patients, as well as provided new insights into approaches to develop new immunotherapies for patients with gastrointestinal cancer.

Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.

Perinatal hypoxic-ischaemic encephalopathy is the leading cause of neonatal death and permanent neurological deficits, while the basal ganglia is one of the major nuclei that is selectively and greatly affected in the brains of hypoxic-ischaemic encephalopathy patients, especially in severe cases. Human embryonic stem cell-derived neurons have shown great potential in different types of brain disorders in adults. However, it remains unknown whether and how grafted human embryonic stem cell-derived neurons can repair immature brains with hypoxic-ischaemic encephalopathy. Here, by administrating genetically labelled human embryonic stem cell-derived striatal neural progenitors into the ipsilateral striatum of hypoxic-ischaemic encephalopathy-injured mice, we found that the grafted cells gradually matured into GABA spiny projection neurons morphologically and electrophysiologically, and significantly rescued the area loss of hypoxic-ischaemic encephalopathy-injured brains. Intriguingly, using immunohistochemical staining combined with enhanced ascorbate peroxidase-based immunoelectron microscopy and rabies virus-mediated trans-synaptic tracing, we show that the grafts start to extend axonal projections to the endogenous target areas (globus pallidus externa, globus pallidus internus, substantia nigra), form synapses with host striatal, globus pallidus and nigra neurons, and receive extensive and stable synaptic inputs as early as 2 months post-transplantation. Importantly, we further demonstrated functional neural circuits re-established between the grafted neurons and host cortical, striatal and substantial nigra neurons at 3-6 months post-transplantation in the hypoxic-ischaemic encephalopathy-injured brain by optogenetics combined with electrophysiological recording. Finally, the transplanted striatal spiny projection neurons but not spinal GABA neurons restored the motor defects of hypoxic-ischaemic encephalopathy, which were reversed by clozapine-N-oxide-based inhibition of graft function. These findings demonstrate anatomical and functional reconstruction of the basal ganglia neural circuit including multiple loops by striatal spiny projection neurons in hypoxic-ischaemic encephalopathy-injured immature brains, which raises the possibility of such a cell replacement therapeutic strategy for hypoxic-ischaemic encephalopathy in neonates.

Recent Developments on the Roles of Calcium Signals and Potential Therapy Targets in Cervical Cancer.

Intracellular calcium (Ca2+) concentration ([Ca2+]i) is implicated in proliferation, invasion, and metastasis in cancerous tissues. A variety of oncologic therapies and some candidate drugs induce their antitumor effects (in part or in whole) through the modulation of [Ca2+]i. Cervical cancer is one of most common cancers among women worldwide. Recently, major research advances relating to the Ca2+ signals in cervical cancer are emerging. In this review, we comprehensively describe the current progress concerning the roles of Ca2+ signals in the occurrence, development, and prognosis of cervical cancer. It will enhance our understanding of the causative mechanism of Ca2+ signals in cervical cancer and thus provide new sights for identifying potential therapeutic targets for drug discovery.

A Novel Minimum Spanning Tree Clustering Algorithm Based on Density Core.

Clustering analysis is an unsupervised learning method, which has applications across many fields such as pattern recognition, machine learning, information security, and image segmentation. The density-based method, as one of the various clustering algorithms, has achieved good performance. However, it works poor in dealing with multidensity and complex-shaped datasets. Moreover, the result of this method depends heavily on the parameters we input. Thus, we propose a novel clustering algorithm (called the MST-DC) in this paper, which is based on the density core. Firstly, we employ the reverse nearest neighbors to extract core objects. Secondly, we use the minimum spanning tree algorithm to cluster the core objects. Finally, the remaining objects are assigned to the cluster to which their nearest core object belongs. The experimental results on several synthetic and real-world datasets show the superiority of the MST-DC to Kmeans, DBSCAN, DPC, DCore, SNNDPC, and LDP-MST.

Research progress of placental vascular pathophysiological changes in pregnancy-induced hypertension and gestational diabetes mellitus.

The placenta is a vital organ for fetal development, providing the fetus with nutrients, oxygen, and other important factors. Placenta is rich in blood vessels. Abnormal placental vascular function and blood circulation may lead to insufficient blood supply to the fetus in the uterus, leading to serious consequences such as pregnancy complications, fetal distress and even stillbirth. Pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM) are common complications of pregnancy. Recent studies report that pregnancy complications are often accompanied by changes in placental vascular structure and function. What are the physiological characteristics of human placental blood vessels? What are the pathological changes in the state of PIH and GDM? What are the relationships between these pathological changes and the occurrence of these pregnancy complications? Answers to these questions not only increase the understanding of placental vascular characteristics, but also provide important information for revealing the pathological mechanism of PIH and GDM. This article will summarize the research on the pathological changes of placental blood vessels in PIH and GDM, hoping to further unravel the physiological and pathological characteristics of placental blood vessels in the state of PIH and GDM, provide information for guiding clinical treatment for PIH and GDM.

Prenatal hypothyroidism diminished exogenous NO-mediated diastolic effects in fetal rat thoracic aorta smooth muscle via increased oxidative stress.

Maternal hypothyroidism is an important problem of modern healthcare and is reported to increase the risk of cardiovascular diseases in the offspring later in life. However, it is unclear whether hypothyroidism during pregnancy causes vascular damage in the fetal period. We established the prenatal hypothyroidism rat model and collected the fetuses at the 21th day of gestation (GD21). Thyroid hormone concentrations in maternal and offspring blood serum were assessed by enzyme-linked immunosorbent assay (ELISA). The thoracic aortas of the fetuses were isolated for microvessel functional testing and histochemical stainings. qPCR and Western blot were performed to access mRNA and protein expression. We found that the concentrations of thyroid hormones in the serum of pregnant rats and fetuses were significantly suppressed at GD21. The responses of the fetal thoracic aortas to SNP were significantly attenuated in the PTU group. However, no statistical difference was found between the two groups when treated with either inhibitor (ODQ) or activator (BAY58-2667) of sGC. The production of O2-• in the arterial wall was significantly increased in hypothyroid fetuses. Moreover, the level of NADPH oxidase (NOX) was increased, while superoxide dismutase 2 (SOD2) was down-regulated in the PTU group, ultimately contributing to the increased production of superoxide. Additionally, decreased SNP-mediated vasodilation found in fetal vessels was improved by either NOX inhibitor (Apocynin) or SOD mimic (Tempol). These results indicate that increased oxidative stress is probably the cause of the diminished diastolic effect of exogenous NO in the thoracic artery of prenatal hypothyroidism exposed fetuses.

Research Progress of DNA Methylation in Endometrial Cancer.

Endometrial cancer (EC)) is one of the most common malignant tumors of the female genital system, with an increasing incidence and mortality, worldwide. Although the therapeutic strategy of EC is still complicated and challenging, further understanding of carcinogenesis from a gene perspective would allow an effort to improve therapeutic precision in this complex malignancy. DNA methylation is the most widely studied epigenetic alteration in human tumors. Aberrant DNA methylation events, resulting in altered gene expression, are features of many tumor types. In this review, we provide an update on evidence about the roles of aberrant DNA methylation within some classical tumor suppressor genes and oncogenes in endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to EC, as well as opportunities and challenges of DNA methylation in EC management and prevention.

Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcomes in a Parkinson's disease model.

Human pluripotent stem cell-based (hPSC-based) replacement therapy holds great promise for the treatment of Parkinson's disease (PD). However, the heterogeneity of hPSC-derived donor cells and the low yield of midbrain dopaminergic (mDA) neurons after transplantation hinder its broad clinical application. Here, we have characterized the single-cell molecular landscape during mDA neuron differentiation. We found that this process recapitulated the development of multiple but adjacent fetal brain regions including the ventral midbrain, the isthmus, and the ventral hindbrain, resulting in a heterogenous donor cell population. We reconstructed the differentiation trajectory of the mDA lineage and identified calsyntenin 2 (CLSTN2) and protein tyrosine phosphatase receptor type O (PTPRO) as specific surface markers of mDA progenitors, which were predictive of mDA neuron differentiation and could facilitate high enrichment of mDA neurons (up to 80%) following progenitor cell sorting and transplantation. Marker-sorted progenitors exhibited higher therapeutic potency in correcting motor deficits of PD mice. Different marker-sorted grafts had a strikingly consistent cellular composition, in which mDA neurons were enriched, while off-target neuron types were mostly depleted, suggesting stable graft outcomes. Our study provides a better understanding of cellular heterogeneity during mDA neuron differentiation and establishes a strategy to generate highly purified donor cells to achieve stable and predictable therapeutic outcomes, raising the prospect of hPSC-based PD cell replacement therapies.

Unveiling the Role of DNA Methylation in Vascular CACNA1C Tissue-Specific Expression.

Objective: Calcium voltage-gated channel subunit alpha1 C (CACNA1C) plays a critical role in many vascular physiological and pathological processes. Determining its tissue-specific expression pattern and clarifying the underlying molecular mechanisms are necessary and meaningful. Methods: We selected several representative vessels from normal male Sprague-Dawley rats. Vessel tissue or primary vascular smooth muscle cells were isolated for vascular function, electrophysiology, gene expression and promoter methylation studies. Results: We found CACNA1C had tissue-specific expressions in vessels. The specific manifestations were as follows: CACNA1C expression was highest in thoracic aorta, second lowest in middle cerebral and pulmonary artery, and lowest in mesenteric artery. Excitingly, an opposing trend was observed between CACNA1C expression and its promoter methylation. Conclusions: This study was the first report to indicate that DNA methylation could be involved in regulating CACNA1C tissue-specific expressions and vasoconstriction function in vascular system. This study not only provided more information for further understanding the physiological characteristics of vascular CACNA1C expressions, also strengthened the idea that DNA methylation plays important roles in regulating vascular smooth muscle cells function and the consequent occurrence of vascular diseases.

Antenatal Dexamethasone Exposure Impairs Vascular Contractile Functions via Upregulating IP3 Receptor 1 and Cav1.2 in Adult Male Offspring.

BACKGROUND: Administration of antenatal glucocorticoids remains common practice for treating preterm delivery. Antenatal glucocorticoid exposure increased the risk of developing vascular diseases in later life, but the precise mechanisms remain unclear. This study aimed to explore the effects and mechanisms of antenatal exposure to clinically relevant doses of dexamethasone (synthetic glucocorticoids) on vascular functions in adult male offspring. METHODS: Pregnant Sprague-Dawley rats received dexamethasone or vehicle during the last week of pregnancy. Male offspring were killed at gestational day 21 (Fetus) or postnatal day 120 (adult offspring). Mesenteric arteries were collected for vascular function, electrophysiology, target gene expression, and promotor methylation studies. RESULTS: Antenatal dexamethasone exposure increased phenylephrine-mediated vascular contractility in offspring, which was resulted by the activated inositol 1,4,5-trisphosphate (IP3) receptor and L-type Ca2+ channels. Specifically, increases of IP3R1 (IP3 receptor 1) and Cav1.2 (L-type Ca2+ channels subunit alpha1 C) were responsible for an activated IP3-Ca2+ pathway in the vasculature, and eventually predisposed the antenatal dexamethasone offspring to vascular hypercontractility. In addition, IP3R1 and Cav1.2 was upregulated through transcriptional mechanism; the overall changes in promotor histone modifications were consistent with the corresponding changes in transcriptional levels of the 2 genes, suggesting that antenatal dexamethasone exposure activated the transcription of IP3R1 and Cav1.2 via altering promotor histone modifications. CONCLUSIONS: Taken together, this study demonstrated that antenatal dexamethasone exposure resulted in vascular adverse outcomes in male offspring that is linked to the increases of IP3R1 and Cav1.2 mediated by epigenetic modifications in the vasculature.