The uteroplacental circulation at high altitude: adaptation and maladaptation.

The greatest challenge of living at high altitude is hypoxia. Hypoxia imposes immense impacts on reproduction. Gestation at high altitude is associated with high incidence of fetal growth restriction (FGR) and pre-eclampsia owing to maladaptation of uteroplacental circulation/placenta insufficiency and oxygen delivery to the fetus.

MicroRNA-210 Mediates Hypoxic Pulmonary Hypertension in the Newborn Lamb.

Background: Pulmonary hypertension of the newborn is a life-threatening disorder characterized by elevated pulmonary vascular resistance due to maladaptation of the pulmonary circulation after birth. The pathogenesis and mechanisms underlying pulmonary hypertension of the newborn remain unclear, hindering the development of effective treatment. We hypothesize that perinatal chronic hypoxia upregulates microRNA-210, which is essential for suppression of pulmonary arterial spontaneous transient outward currents (STOCs), resulting in pulmonary hypertension of the newborn.

Rad-mediated inhibition of Ca1.2 channel activity contributes to uterine artery haemodynamic adaptation to pregnancy.

The striking increase of uterine blood flow during pregnancy is essential for normal fetal development as well as for cardiovascular well-being of the mother. Yet, the underlying mechanisms of pregnancy-mediated vasodilatation of the uterine artery are not fully understood. In this study, we test the hypothesis that Rad, a monomeric G protein, is a novel regulatory mechanism in inhibiting Ca1.

Fetal hypoxia results in sex- and cell type-specific alterations in neonatal transcription in rat oligodendrocyte precursor cells, microglia, neurons, and oligodendrocytes.

Background: Fetal hypoxia causes vital, systemic, developmental malformations in the fetus, particularly in the brain, and increases the risk of diseases in later life. We previously demonstrated that fetal hypoxia exposure increases the susceptibility of the neonatal brain to hypoxic-ischemic insult. Herein, we investigate the effect of fetal hypoxia on programming of cell-specific transcriptomes in the brain of neonatal rats.

TET2 confers a mechanistic link of microRNA-210 and mtROS in hypoxia-suppressed spontaneous transient outward currents in uterine arteries of pregnant sheep.

Hypoxia during pregnancy impairs uterine vascular adaptation via microRNA-210 (miR-210)-mediated mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) generation. TET methylcytosine dioxygenase 2 (TET2) participates in regulating inflammation and oxidative stress and its deficiency contributes to the pathogenesis of multiple cardiovascular diseases. Thus, we hypothesize a role of TET2 in hypoxia/miR-210-mediated mtROS suppressing spontaneous transient outward currents (STOCs) in uterine arteries.

MicroRNA-210-mediated mtROS confer hypoxia-induced suppression of STOCs in ovine uterine arteries.

Background And Purpose: Hypoxia during pregnancy is associated with increased uterine vascular resistance and elevated blood pressure both in women and female sheep. A previous study demonstrated a causal role of microRNA-210 (miR-210) in gestational hypoxia-induced suppression of Ca sparks/spontaneous transient outward currents (STOCs) in ovine uterine arteries, but the underlying mechanisms remain undetermined. We tested the hypothesis that miR-210 perturbs mitochondrial metabolism and increases mitochondrial reactive oxygen species (mtROS) that confer hypoxia-induced suppression of STOCs in uterine arteries.

MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction.

Background: Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux.

Methods: Myocardial infarction in an acute setting of IR was examined through comparing loss- versus gain-of-function experiments in microRNA-210-deficient and wild-type mice.

MicroRNA-210 Mediates Hypoxia-Induced Repression of Spontaneous Transient Outward Currents in Sheep Uterine Arteries During Gestation.

[Figure: see text].

MicroRNA-210 downregulates TET2 and contributes to inflammatory response in neonatal hypoxic-ischemic brain injury.

Background: Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns. Our previous studies demonstrated that HI insult significantly increased microRNA-210 (miR-210) in the brain of rat pups and inhibition of brain endogenous miR-210 by its inhibitor (LNA) provided neuroprotective effect in HI-induced brain injury. However, the molecular mechanisms underpinning this neuroprotection remain unclear.

Gestational Hypoxia Inhibits Pregnancy-Induced Upregulation of Ca Sparks and Spontaneous Transient Outward Currents in Uterine Arteries Via Heightened Endoplasmic Reticulum/Oxidative Stress.

Hypoxia during pregnancy profoundly affects uterine vascular adaptation and increases the risk of pregnancy complications, including preeclampsia and fetal intrauterine growth restriction. We recently demonstrated that increases in Ca sparks and spontaneous transient outward currents (STOCs) played an essential role in pregnancy-induced uterine vascular adaptation. In the present study, we hypothesize that gestational hypoxia suppresses Ca sparks/STOCs coupling leading to increased uterine vascular tone via enhanced endoplasmic reticulum (ER)/oxidative stress.

Multi-Omics Integration Reveals Short and Long-Term Effects of Gestational Hypoxia on the Heart Development.

Antenatal hypoxia caused epigenetic reprogramming of methylome and transcriptome in the developing heart and increased the risk of heart disease later in life. Herein, we investigated the impact of gestational hypoxia in proteome and metabolome in the hearts of fetus and adult offspring. Pregnant rats were treated with normoxia or hypoxia (10.

MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy.

Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy (HIE). However, the immunological mechanisms that underlie HIE remain unclear. MicroRNA-210 (miR-210) is the master "hypoxamir" and plays a key role in hypoxic-ischemic tissue damage.

Antenatal Hypoxia and Programming of Glucocorticoid Receptor Expression in the Adult Rat Heart.

Glucocorticoid receptor (GR) signaling is critical for development and function of the heart. Our previous study demonstrated that gestational hypoxia induced epigenetic repression of the GR gene in the developing heart. The present study aims to determine that the alterations of promoter methylation level and epigenetic repression of the GR gene in the developing heart in response to maternal hypoxia is sustained in adult offspring and potential gender differences in the programming of GR gene.

Epigenetic down-regulation of BK channel by miR-181a contributes to the fetal and neonatal nicotine-mediated exaggerated coronary vascular tone in adult life.

Background: Fetal origin of adult cardiovascular disease is one of the most pressing public concerns and economic problem in modern life. Maternal cigarette smoking/nicotine abuse increases the risk of cardiovascular disease in offspring. However, the underlying mechanisms and theranostics remain unclear.

Pregnancy Increases Ca Sparks/Spontaneous Transient Outward Currents and Reduces Uterine Arterial Myogenic Tone.

Spontaneous transient outward currents (STOCs) at physiological membrane potentials of vascular smooth muscle cells fundamentally regulate vascular myogenic tone and blood flow in an organ. We hypothesize that heightened STOCs play a key role in uterine vascular adaptation to pregnancy. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep.

MicroRNA-210 Downregulates ISCU and Induces Mitochondrial Dysfunction and Neuronal Death in Neonatal Hypoxic-Ischemic Brain Injury.

Neonatal hypoxic-ischemic (HI) brain injury causes significant mortality and long-term neurologic sequelae. We previously demonstrated that HI significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of brain endogenous miR-210 was neuroprotective in HI brain injury. However, the molecular mechanisms underpinning this neuroprotection remain unclear.

Foetal hypoxia impacts methylome and transcriptome in developmental programming of heart disease.

Aims: Antenatal hypoxia negatively impacts foetal heart development, and increases the risk of heart disease later in life. The molecular mechanisms remain largely elusive. Here, we conducted a genome-wide analysis to study the impact of antenatal hypoxia on DNA methylome and transcriptome profiling in foetal and adult offspring hearts.

Long-term high altitude hypoxia during gestation suppresses large conductance Ca -activated K channel function in uterine arteries: a causal role for microRNA-210.

Key Points: Gestational hypoxia represses ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which is recovered by inhibiting endogenous miR-210. Inhibition of miR-210 rescues BK channel expression and current in uterine arteries of pregnant animals acclimatized to high altitude hypoxia in a TET-dependent manner. miR-210 blockade restores BK channel-mediated relaxations and attenuates pressure-dependent myogenic tone in uterine arteries of pregnant animals acclimatized to high altitude.

SIRT1 increases cardiomyocyte binucleation in the heart development.

SIRT1 regulates cell senescence. We investigated a novel role of SIRT1 in the regulation of cardiomyocyte terminal differentiation in the developing heart. Retinoic acid (RA)-induced binucleation of H9c2 cells was associated with increased SIRT1 expression.

Role of DNA methylation in perinatal nicotine-induced development of heart ischemia-sensitive phenotype in rat offspring.

Background And Purpose: Maternal cigarette smoking increases the risk of cardiovascular disease in offspring. Recently, we have demonstrated that perinatal nicotine exposure alters heart development and increases heart susceptibility to ischemia/reperfusion (I/R) injury in rat offspring. The present study tested the hypothesis that DNA methylation plays a key role in the nicotine-induced development of heart ischemia-sensitive phenotype in offspring.

MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca-Activated K Channel Expression and Function in Ovine Uterine Arteries.

Gestational hypoxia inhibits large conductance Ca-activated K (BK) channel expression and function in uterine arterial adaptation to pregnancy. Given the findings that microRNA-210 (miR-210) is increased in hypoxia during gestation and preeclampsia, the present study sought to investigate the role of miR-210 in the regulation of BK channel adaptation in the uterine artery. Gestational hypoxia significantly increased uterine vascular resistance and blood pressure in pregnant sheep and upregulated miR-210 in uterine arteries.

MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury.

Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain.

Pregnancy Reprograms Large-Conductance Ca-Activated K Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation.

The large-conductance Ca-activated K (BK) channel is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood flow. The present study tested the hypothesis that active DNA demethylation plays a key role in pregnancy-induced reprogramming and upregulation of BK channel β1 subunit (BKβ1) in uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep.

Chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca2+-activated K+ channel function in ovine uterine arteries.

Chronic hypoxia during gestation suppresses large-conductance Ca2+-activated K+ (BKCa) channel function and impedes uterine arterial adaptation to pregnancy. This study tested the hypothesis that chronic hypoxia has a direct effect in upregulating DNA methyltransferase (DNMT) and epigenetically repressing BKCa channel beta-1 subunit (KCNMB1) expression in uterine arteries. Resistance-sized uterine arteries were isolated from near-term pregnant sheep maintained at ∼300 m above sea level or animals acclimatized to high-altitude (3,801 m) hypoxia for 110 days during gestation.