Explore the vast range of titles available.

Placental hypoxia can stimulate oxidative stress and mitochondrial dysfunction reducing placental efficiency and inducing fetal growth restriction (FGR). We hypothesized that chronic hypoxia inhibits mitochondrial function in the placenta as an underlying cause of cellular mechanisms contributing to FGR. Pregnant guinea pigs were exposed to either normoxia (NMX) or hypoxia (HPX; 10.5% O2) at 25 day gestation until term (65 day). Guinea pigs were anesthetized, and fetuses and placentas were excised at either mid (40 day) or late gestation (64 day), weighed, and placental tissue stored at –80°C until assayed. Mitochondrial DNA content, protein expression of respiratory Complexes I-V, and nitration and activity rates of Complexes I and IV were measured in NMX and HPX male (N = 6 in each treatment) and female (N = 6 in each treatment) placentas. Mitochondrial density was not altered by HPX in either mid- or late-term placentas. In mid gestation, HPX slightly increased expression of Complexes I-III and V in male placentas only, but had no effect on either Complex I or IV activity rates or nitrotyrosine expression. In late gestation, HPX significantly decreased CI/CIV activity rates and increased CI/CIV nitration in male but not female placentas exhibiting a sexual dimorphism. Complex I-V expression was reduced from mid to late gestation in both male and female placentas regardless of treatment. We conclude that chronic HPX decreases mitochondrial function by inhibiting Complex I/IV activity via increased peroxynitrite in a sex-related manner. Further, there may be a progressive decrease in energy metabolism of placental cell types with gestation that increases the vulnerability of placental function to intrauterine stress. Summary Sentence Chronic maternal hypoxia impairs mitochondrial function as an underlying cause of placental dysfunction, which may contribute to altered placental and fetal growth.

Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0–16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress, and autophagy in GCs in the adult ovary. RNA sequencing analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated granulosa cells isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary. Summary Sentence Autophagy induced ovarian GC death in fetal hypoxic female offspring through the Hif1a pathway. Graphical Abstract

Fetal hypoxia and maternal stress frequently culminate in neuropsychiatric afflictions in life. To replicate this condition, we employed a model of prenatal severe hypoxia (PSH) during days 14–16 of rat gestation. Subsequently, both control and PSH rats at 3 months old were subjected to episodes of inescapable stress to induce learned helplessness (LH). The results of the open field test revealed an inclination towards depressive-like behavior in PSH rats. Following LH episodes, control (but not PSH) rats displayed significant anxiety. LH induced an increase in glucocorticoid receptor (GR) levels in extrahypothalamic brain structures, with enhanced nuclear translocation in the hippocampus (HPC) observed both in control and PSH rats. However, only control rats showed an increase in GR nuclear translocation in the amygdala (AMG). The decreased GR levels in the HPC of PSH rats correlated with elevated levels of hypothalamic corticotropin-releasing hormone (CRH) compared with the controls. However, LH resulted in a reduction of the CRH levels in PSH rats, aligning them with those of control rats, without affecting the latter. This study presents evidence that PSH leads to depressive-like behavior in rats, associated with alterations in the glucocorticoid system. Notably, these impairments also contribute to increased resistance to severe stressors.

Evidence derived from human clinical studies and experimental animal models shows a causal relationship between adverse pregnancy and increased cardiovascular disease in the adult offspring. However, translational studies isolating mechanisms to design intervention are lacking. Sheep and humans share similar precocial developmental milestones in cardiovascular anatomy and physiology. We tested the hypothesis in sheep that maternal treatment with antioxidants protects against fetal growth restriction and programmed hypertension in adulthood in gestation complicated by chronic fetal hypoxia, the most common adverse consequence in human pregnancy. Using bespoke isobaric chambers, chronically catheterized sheep carrying singletons underwent normoxia or hypoxia (10% oxygen [O2]) ± vitamin C treatment (maternal 200 mg.kg-1 IV daily) for the last third of gestation. In one cohort, the maternal arterial blood gas status, the value at which 50% of the maternal hemoglobin is saturated with oxygen (P50), nitric oxide (NO) bioavailability, oxidative stress, and antioxidant capacity were determined. In another, naturally delivered offspring were raised under normoxia until early adulthood (9 months). Lambs were chronically instrumented and cardiovascular function tested in vivo. Following euthanasia, femoral arterial segments were isolated and endothelial function determined by wire myography. Hypoxic pregnancy induced fetal growth restriction and fetal oxidative stress. At adulthood, it programmed hypertension by enhancing vasoconstrictor reactivity and impairing NO-independent endothelial function. Maternal vitamin C in hypoxic pregnancy improved transplacental oxygenation and enhanced fetal antioxidant capacity while increasing NO bioavailability, offsetting constrictor hyper-reactivity and replenishing endothelial function in the adult offspring. These discoveries provide novel insight into mechanisms and interventions against fetal growth restriction and adult-onset programmed hypertension in an animal model of complicated pregnancy in a species of similar temporal developmental milestones to humans.

Expression of apoptotic protease activating factor-1 (Apaf-1) gradually decreases during brain development, and this decrease is likely responsible for the decreased sensitivity of brain tissue to apoptosis. However, the mechanism by which Apaf-1 expression is decreased remains elusive. In the present study, we found that four microRNAs (miR-23a/b and miR-27a/b) of miR-23a-27a-24 and miR-23b-27b-24 clusters play key roles in modulating the expression of Apaf-1. First, we found that miR-23a/b and miR-27a/b suppressed the expression of Apaf-1 in vitro . Interestingly, the expression of the miR-23-27-24 clusters in the mouse cortex gradually increased in a manner that was inversely correlated with the pattern of Apaf-1 expression. Second, hypoxic injuries during fetal distress caused reduced expression of the miR-23b and miR-27b that was inversely correlated with an elevation of Apaf-1 expression during neuronal apoptosis. Third, we made neuronal-specific transgenic mice and found that overexpressing the miR-23b and miR-27b in mouse neurons inhibited the neuronal apoptosis induced by intrauterine hypoxia. In conclusion, our results demonstrate, in central neural system, that miR-23a/b and miR-27a/b are endogenous inhibitory factors of Apaf-1 expression and regulate the sensitivity of neurons to apoptosis. Our findings may also have implications for the potential target role of microRNAs in the treatment of neuronal apoptosis-related diseases.

Fetal hypoxia, a major contributor to neonatal mortality, induces complex neurovascular disruptions in developing brains, yet human-specific cellular mechanisms remain poorly understood due to limitations in existing models. This study establishes an advanced vascularized human cortical organoid (vhCO) model to decode cell type-specific injury mechanisms and therapeutic targets during hypoxia-reoxygenation. We developed vhCOs by integrating cortical and vascular organoids, recapitulating mid-to-late gestational neurodevelopment with diverse lineages-neural progenitors, neurons, microglia, and functional vasculature with blood-brain barrier properties. Hypoxia-reoxygenation experiments were conducted on vhCOs, followed by single-cell transcriptomic profiling to dissect cellular responses. Key findings include: (1) Lineage-specific vulnerabilities: astrocyte precursors exhibited developmental arrest, while immature GABAergic neurons (Subtype I) underwent neurogenic collapse. Microglia displayed a biphasic inflammatory response-initially suppressed, then hyperactivated post-reoxygenation, diverging from animal models; (2) Hypoxia memory persisted in non-neural cells (pericytes, fibroblasts), driving compartment-specific vascular remodeling via Notch signaling and collagen deposition; (3) Rewired neural-non-neural crosstalk networks (e.g., IGF2-IGF2R, LGALS3-MERTK, Wnts-SFRP2) revealed novel repair targets inaccessible to conventional models. By prioritizing single-cell resolution, this study delineates human-specific neurovascular pathophysiology and stress adaptation networks in hypoxic brain injury. The vhCO platform bridges translational gaps, offering a paradigm for precision therapeutics and advancing research on developmental brain disorders.

Pro-inflammatory cytokines contribute to hypoxic–ischemic brain injury. Blood–brain barrier (BBB) dysfunction represents an important component of hypoxic–ischemic brain injury in the fetus. Hypoxic–ischemic injury could accentuate systemic cytokine transfer across the fetal BBB. There has been considerable conjecture suggesting that systemic cytokines could cross the BBB during the perinatal period. Nonetheless, evidence to support this contention is sparse. We hypothesized that ischemia–reperfusion increases the transfer of systemic interleukin-1β (IL-1β) across the BBB in the fetus. Ovine fetuses at 127 days of gestation were studied 4 hours after 30 minutes of bilateral carotid artery occlusion and compared with a nonischemic group. Recombinant ovine IL-1β protein was expressed from an IL-1β pGEX-2 T vector in E. coli BL-21 cells and purified. The BBB function was quantified in 12 brain regions using a blood-to-brain transfer constant with intravenous 125I-radiolabeled IL-1β (125I-IL-1β). Interleukin-1β crossed the intact BBB in nonischemic fetuses. Blood-to-brain transport of 125I-IL-1β was higher (P < 0.05) across brain regions in fetuses exposed to ischemia–reperfusion than nonischemic fetuses. We conclude that systemic IL-1β crosses the intact fetal BBB, and that ischemia–reperfusion increases transfer of this cytokine across the fetal BBB. Therefore, altered BBB function after hypoxia–ischemia facilitates entry of systemic cytokines into the brain of the fetus.

Gestational stressors, including glucocorticoids and protein restriction, can affect kidney development and hence final nephron number. Since hypoxia is a common insult during pregnancy, we studied the influence of oxygen tension on kidney development in models designed to represent a pathological hypoxic insult. In vivo mouse models of moderate, transient, midgestational (12% O2, 48h, 12.5dpc) or severe, acute, early-gestational (5.5–7.5% O2, 8h, 9.5–10.5dpc) hypoxia were developed. The embryo itself is known to mature under hypoxic conditions with embryonic tissue levels of oxygen estimated to be 5%–8% (physiological hypoxia) when the mother is exposed to ambient normoxia. Both in vivo models generated phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT). Severe, acute, early hypoxia resulted in duplex kidney, while moderate, transient, midgestational hypoxia permanently reduced ureteric branching and nephron formation. Both models displayed hypoxia-induced reductions in β-catenin signaling within the ureteric tree and suppression of the downstream target gene, Ccnd1. Thus, we show a link between gestational hypoxia and CAKUT, the phenotype of which varies with timing, duration, and severity of the hypoxic insult.

BackgroundIntrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is reduced, and offspring from IUGR pregnancies are at increased risk for type II diabetes as adults. The liver is susceptible to fetal undernutrition experienced by IUGR infants and animal models of growth restriction. This study aimed to examine hepatic expression changes in a maternal nutrient restriction (MNR) mouse model of IUGR to understand fetal adaptations that influence adult metabolism.MethodsLiver samples of male offspring from MNR (70% of ad libitum starting at E6.5) or control pregnancies were obtained at E18.5 and differential expression was assessed by RNAseq and western blots.ResultsForty-nine differentially expressed (FDR < 0.1) transcripts were enriched in hypoxia-inducible pathways including Fkbp5 (1.6-fold change), Ccng2 (1.5-fold change), Pfkfb3 (1.5-fold change), Kdm3a (1.2-fold change), Btg2 (1.6-fold change), Vhl (1.3-fold change), and Hif-3a (1.3-fold change) (FDR < 0.1). Fkbp5, Pfkfb3, Kdm3a, and Hif-3a were confirmed by qPCR, but only HIF-2a (2.2-fold change, p = 0.002) and HIF-3a (1.3 p = 0.03) protein were significantly increased.ConclusionAlthough a moderate impact, these data support evidence of fetal adaptation to reduced nutrients by increased hypoxia signaling in the liver.

Intrauterine hypoxia (gestation days 15-19, pO 2 65 mm Hg, duration 4 h) led to an increase in the expression of p53, beclin-1, endothelial NO synthase (eNOS), and caspase-3 proteins in cardiomyocytes and reduced the number of mast cells in the heart of 60-day-old albino rats. Administration of a non-opiate analogue of leu-enkephalin (NALE peptide: Phe–D-Ala–Gly–Phe–Leu–Arg, 100 μg/kg) on days 2-6 of the neonatal period decreased the severity of delayed posthypoxic myocardial reaction. The content of eNOS + cardiomyocytes and the total number of mast cells of these animals did not differ from the control parameters; the content of p53 + cardiomyocytes was significantly lower than in animals exposed to intrauterine hypoxia. The cardioprotective activity of NALE was partially neutralized by co-administration with the NO synthase inhibitor (L-NAME, 50 mg/kg). Correction of the delayed posthypoxic changes, similar to the effects of NALE peptide, was observed after neonatal administration of its arginine-free analogue, G peptide (Phe–D-Ala–Gly–Phe–Leu–Gly; 100 μg/kg). Non-opiate analogues of leu-enkephalin NALE and G peptides can be considered as promising substances capable of preventing long-term cardiac consequences of intrauterine hypoxia.