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The psychoactive component in cannabis, delta‐9‐tetrahydrocannabinol, can restrict fetal growth and development. Delta‐9‐tetrahydrocannabinol has been shown to negatively impact cellular proliferation and target organelles like the mitochondria resulting in reduced cellular respiration. In the placenta, mitochondrial dysfunction leading to oxidative stress prevents proper placental development and function. A key element of placental development is the proliferation and fusion of cytotrophoblasts to form the syncytium that comprises the materno‐fetal interface. The impact of delta‐9‐tetrahydrocannabinol on this process is not well understood. To elucidate the nature of the mitochondrial dysfunction and its consequences on trophoblast fusion, we treated undifferentiated and differentiated BeWo human trophoblast cells, with 20 µM delta‐9‐tetrahydrocannabinol for 48 hr. At this concentration, delta‐9‐tetrahydrocannabinol on BeWo cells reduced the expression of markers involved in syncytialization and mitochondrial dynamics, but had no effect on cell viability. Delta‐9‐tetrahydrocannabinol significantly attenuated the process of syncytialization and induced oxidative stress responses in BeWo cells. Importantly, delta‐9‐tetrahydrocannabinol also caused a reduction in the secretion of human chorionic gonadotropin and the production of human placental lactogen and insulin growth factor 2, three hormones known to be important in facilitating fetal growth. Furthermore, we also demonstrate that delta‐9‐tetrahydrocannabinol attenuated mitochondrial respiration, depleted adenosine triphosphate, and reduced mitochondrial membrane potential. These changes were also associated with an increase in cellular reactive oxygen species, and the expression of stress responsive chaperones, HSP60 and HSP70. These findings have important implications for understanding the role of delta‐9‐tetrahydrocannabinol‐induced mitochondrial injury and the role this might play in compromising human pregnancies. THC disrupted mitochondrial function, increased markers of mitochondrial fission and cellular stress in BeWo cells. This was coincident with reduced BeWo cell fusion and secretion of important fetal growth signals, hPL and IGF2. These changes were mediated, in part, via the CB1 receptor in syncytialized BeWo cells.

Progress in the study of pregnancy complicated by chronic hypoxia in large mammals has been held back by the inability to measure long‐term significant reductions in fetal oxygenation at values similar to those measured in human pregnancy complicated by fetal growth restriction. Here, we introduce a technique for physiological research able to maintain chronically instrumented maternal and fetal sheep for prolonged periods of gestation under significant and controlled isolated chronic hypoxia beyond levels that can be achieved by habitable high altitude. This model of chronic hypoxia permits measurement of materno‐fetal blood gases as the challenge is actually occurring. Chronic hypoxia of this magnitude and duration using this model recapitulates the significant asymmetric growth restriction, the pronounced cardiomyopathy, and the loss of endothelial function measured in offspring of high‐risk pregnancy in humans, opening a new window of therapeutic research. We introduce a technique for physiological research able to maintain chronically instrumented maternal and fetal sheep for prolonged periods of gestation under significant and controlled isolated chronic hypoxia beyond levels that can be achieved by habitable high altitude. This model of chronic hypoxia permits measurement of materno‐fetal blood gases as the challenge is actually occurring. Chronic hypoxia of this magnitude and duration using this model recapitulates the significant asymmetric growth restriction, the pronounced cardiomyopathy, and the loss of endothelial function measured in offspring of high‐risk pregnancy in humans, opening a new window of therapeutic research.

Performing regular exercise is associated with numerous health benefits including a reduction in all‐cause mortality. The mechanisms associated with exercise‐induced health improvements are wide ranging and benefit virtually every organ system in the body. Of significance, recent evidence has suggested that some of these protective benefits may also be passed to offspring through multiple generations via alterations in gamete presentation, changes to the in‐utero and offspring rearing environments, and epigenetic modifications. The purpose of this review was to systematically examine the current literature for evidence of exercise‐induced epigenetic modifications in offspring. A systematic search yielded four papers that met inclusion criteria. Parental exercise interventions were associated with differential DNA methylation patterns in offspring. These shifts in methylation patterns were consistent with concurrent changes in offspring mRNA levels, protein expression, and functional measures. Many of the observed changes were related to metabolic pathways. Hence, the evidence suggests that exercise‐induced epigenetic changes can be observed in offspring and may play a pivotal role among the multifactorial intergenerational‐health impact of exercise. A proposed mechanism for the wide‐ranging health benefits of exercise is epigenetic changes and there is potential for epigenetic changes to be passed on to offspring through intergenerational inheritance.

Aiming to explore ultrasound technology as a noninvasive method for maturation monitoring, we compared ultrasound observations and measurements in female Atlantic salmon (Salmo salar) during the last year before ovulation with standard, invasive methods such as gonadosomatic index (GSI), gonad histology and sex hormone analysis. Ultrasound measurements of ovaries correlated strongly (R > 0.9, P < 0.01) with ovary weight and GSI, and could be used as a noninvasive tool for GSI estimation. Using ultrasound, we were able to identify females with advanced oocyte development and elevated sex hormone and GSI levels earlier than previously observed. Histological studies confirmed these observations showing oocyte yolk accumulation 10 months before ovulation and 8 months before significant increase in sex hormones. Levels of the sex hormone 11‐keto testosterone (11‐KT) indicated a new role of this hormone at final maturation in salmon females. We propose the use of ultrasound as an alternative method to traditionally used invasive methods during sexual maturation monitoring in wild and farmed Atlantic salmon broodstock populations. Eliminating sacrifice of valuable broodfish, and reducing handling stress, would improve animal welfare in present‐day broodstock management. Salmonids, including Atlantic salmon, are of great commercial value, and broodstock management is essential to restoration of wild populations and in egg production in Atlantic salmon farming. At present, the gonado–somatic index (GSI), requiring fish sacrifice, and other invasive methods are commonly used in maturation monitoring in broodstock populations. We have found strong correlations between ultrasound measurements and observations and GSI, sex hormones and oocyte development in maturing Atlantic females, and propose the use of ultrasound in broodstock management as a noninvasive method eliminating the need to sacrifice valuable broodfish and reducing handling stress, thus refining present day maturation monitoring in Atlantic salmon.

Serotonin (5‐HT) contributes to the pathogenesis of experimental neonatal pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD). Platelets are the primary source of circulating 5‐HT and is released upon platelet activation. Platelet transfusions are associated with neonatal mortality and increased rates of BPD. As BPD is often complicated by PH, we tested the hypothesis that circulating platelets are activated and also increased in the lungs of neonatal mice with bleomycin‐induced PH associated with BPD. Newborn wild‐type mice received intraperitoneal bleomycin (3 units/kg) three times weekly for 3 weeks. Platelets from mice with experimental PH exhibited increased adhesion to collagen under flow (at 300 s−1 and 1,500 s−1) and increased expression of the αIIbβ3 integrin and phosphatidylserine, markers of platelet activation. Platelet‐derived factors 5‐HT and platelet factor 4 were increased in plasma from mice with experimental PH. Pharmacologic blockade of the 5‐HT 2A receptor (5‐HT 2A R) prevents bleomycin‐induced PH and pulmonary vascular remodeling. Here, platelets from mice with bleomycin‐induced PH demonstrate increased 5‐HT 2A R expression providing further evidence of both platelet activation and increased 5‐HT signaling in this model. In addition, bleomycin treatment increased lung platelet accumulation. In summary, platelets are activated, granule factors are released, and are increased in numbers in the lungs of mice with experimental neonatal PH. These results suggest platelet activation and release of platelet‐derived factors may increase vascular tone, promote aberrant angiogenesis, and contribute to the development of neonatal PH. Our study utilized a murine bleomycin model of pulmonary hypertension (PH) to study the hypothesis that platelets from mice with PH circulate in an activated state and that circulating and lung platelet‐derived factors, as well as the number of platelets in the lungs of neonatal mice with PH, is significantly increased. Through an extensive characterization of the functional status of platelets from bleomycin‐treated mice, we demonstrate that mice with bleomycin‐induced PH exhibit qualitative but not quantitative platelet changes. Circulating platelets from mice with PH exhibit hyperactivity as measured directly by adhesion and aggregation under flow and the presence of activation markers and indirectly by quantification of platelet‐specific proteins in plasma. Interestingly, we have also found that the absolute number of platelets within the lungs of mice with PH is significantly higher all together suggesting that platelets could directly be promoting PH.

Supplemental oxygen (O2) therapy in preterm infants impairs lung development, but the impact of O2 on long‐term systemic vascular structure and function has not been well‐explored. The present study tested the hypothesis that neonatal O2 therapy induces long‐term structural and functional alterations in the systemic vasculature, resulting in vascular stiffness observed in children and young adults born preterm. Newborn Sprague‐Dawley rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) for 1 and 3 weeks. A subgroup exposed to 3 weeks hyperoxia was recovered in normoxia for an additional 3 weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound and pressure myography. Aorta remodeling was assessed by collagen deposition and expression. Left ventricular (LV) function was assessed by echocardiography. We found that neonatal hyperoxia exposure increased vascular stiffness at 3 weeks, which persisted after normoxic recovery at 6 weeks of age. These findings were accompanied by increased PWV, aortic remodeling, and altered LV function as evidenced by decreased ejection fraction, cardiac output, and stroke volume. Importantly, these functional changes were associated with increased collagen deposition in the aorta. Together, these findings demonstrate that neonatal hyperoxia induces early and sustained biomechanical alterations in the systemic vasculature and impairs LV function. Early identification of preterm infants who are at risk of developing systemic vascular dysfunction will be crucial in developing targeted prevention strategies that may improve the long‐term cardiovascular outcomes in this vulnerable population. Prolonged neonatal oxygen exposure causes persistent aortic structural and biomechanical alterations, which was even more pronounced after recovery in normoxia. This was accompanied by a marked impairment in left ventricular function. These findings have important implications as it suggests that premature babies exposed to oxygen may be predisposed to vascular dysfunction, leading to increased risk of cardiovascular disease in later life. As this affected population begins to age, there will be a critical need to identify the underlying pathophysiological mechanisms for these vascular morbidities in preterm survivors.

Premature infants have a high incidence of bronchopulmonary dysplasia (BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end‐diastolic compliance. This case series studied the usefulness of angiotensin‐converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with “severe” BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23–29 weeks and 505–814 g, respectively. All required mechanical ventilation (including high‐frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements. Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen (55 ± 25 to 29 ± 3%, two‐tailed P = 0.03) and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness [840 ± 94 to 740 ± 83 μm, P = 0.07] and an increased pulsatile diameter [36 ± 14 to 63 ± 25 μm, P = 0.04]). Improvements were observed for both systolic (increased LV output, 188 ± 13 to 208 ± 13 mL/kg/min, P = 0.046 and mean velocity of circumferential fiber shortening, 1.6 ± 0.2 to 2.5 ± 0.3 [circ/sec], P = 0.0004) and diastolic (decreased isovolumic relaxation time, 69.6 ± 8.2 to 59.4 ± 5 msec, P = 0.044) function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance. These findings suggest that improving respiratory and cardiac indices (especially diastolic function) warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy. While bronchopulmonary dysplasia is the most common respiratory sequelae of preterm birth, contribution of systemic arterial thickness/stiffness to its pathophysiology is not well appreciated. This article demonstrates the usefulness of systemic afterload reduction using an angiotensin‐converting enzyme inhibitor (ACE, captopril) in a cohort of infants with “severe” BPD, unresponsive to standard therapy. The role of ACE inhibitors beyond the reduction in blood pressure is discussed.

Previous studies in adult pulmonary hypertension reported that increased hypoxia‐inducible factor–1α (HIF‐1α) signaling contributes to pulmonary vascular remodeling. However, alterations in endothelial HIF‐1α signaling and its contribution to impaired angiogenesis in persistent pulmonary hypertension of the newborn (PPHN) remain unclear. We investigated the hypothesis that HIF‐1α levels are increased in lung endothelial cells in PPHN and contribute to impaired angiogenesis function. We examined HIF‐1α expression and promoter activity in the isolated pulmonary artery endothelial cells (PAEC) from fetal lambs with or without PPHN induced by prenatal ductus arteriosus constriction. We measured the levels of HIF‐1α downstream targets, vascular endothelial growth factor (VEGF) and glycolytic protein, hexokinase 2 (Hek‐2) in PAEC from PPHN, and control lambs. We examined the effect of small interfering‐RNA (siRNA) mediated knockdown of native HIF‐1α on VEGF expression and in vitro angiogenesis function of PPHN‐PAEC. HIF‐1α protein levels were higher in the isolated PAEC from PPHN‐lambs compared to controls. HIF‐1α promoter activity and Hek‐2 protein levels were higher in PPHN. VEGF protein levels and in vitro angiogenesis function were decreased in PAEC from PPHN lambs. HIF‐1α silencing significantly increased the expression of VEGF and improved the angiogenesis function of PPHN PAEC. Aberrant HIF‐1α signaling contributes to endothelial dysfunction and decreased angiogenesis in PPHN. Aberrant HIF‐1α signaling contributes to endothelial dysfunction and decreased angiogenesis in PPHN.

Aim We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages. Methods Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2) from embryonic day E15‐21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro‐sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively. Results Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p < .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1–2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E’/A’ tissue velocities compared to controls (p < .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p < .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p < .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4. Conclusion Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages. In the this study, the impact of chronic fetal hypoxia exposure on myocardial function and aortic stiffness was explored at early postnatal developmental stages using a previously described fetal hypoxia rat model. Fetal hypoxia exposure was associated with progressive LV diastolic dysfunction from 1‐2weeks, which evolved concomitant with changes in nuclear shape and collagen fiber thickness, and with increased aortic stiffness from day 1. These findings are likely relevant to long‐term cardiovascular disease observed following fetal growth restriction.

To examine heart rate variability (HRV) and inflammatory markers as predictors for neurological injury in neonates undergoing therapeutic hypothermia for hypoxic‐ischemic encephalopathy (HIE). We hypothesized that HRV would differentiate between infants with no/mild injury and infants with moderate/severe injury observed on MRI. Because HRV can be associated with the inflammatory cascade, cytokine concentrations were compared with the severity of brain injury indicated by MRI. Further, we studied the effect of temperature, sex, and mechanical ventilation on HRV. HRV was prospectively collected on neonates with HIE using spectral analysis for low and high frequency components (n = 16). A subset (n = 10) of neonates had serum available for inflammatory cytokine analysis obtained during cooling. Neonates were stratified into no/mild or moderate/severe injury based on MRI obtained after rewarming. Differences in HRV were identified; lower low frequency power predicted more injury on MRI. Additionally, in neonates with HIE after cooling procedure, HRV differed by gender. Elevated RANTES (CCL5) and decreased GM‐CSF (Granulocyte‐macrophage colony‐stimulating factor) at 96 hours predicted less severe injury. In this small study, HRV differs between no/mild and moderate/severe injury in neonates with HIE. With further study, this may aid the clinician in real‐time decision making. HRV differs by gender. Finally, inflammatory biomarkers may help elucidate the pathophysiology of HIE. Heart rate variability and inflammatory biomarkers are related to the degree of injury in hypoxic‐ischemic encephalopathy. This is the first study to evaluate infant sex, pressor use and mechanical ventilation when evaluating heart rate variability.