ORCID Profile
0000-0002-1308-1204
Current Organisation
University of Cambridge
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Publisher: Wiley
Date: 13-12-2013
Publisher: Wiley
Date: 03-05-2023
Abstract: Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off‐target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg −1 ), Beta (0.1 mg kg −1 ), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO‐dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin‐1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.
Publisher: Wiley
Date: 12-2015
DOI: 10.14814/PHY2.12614
Publisher: Wiley
Date: 22-10-2021
DOI: 10.1111/JPI.12766
Abstract: Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were ided into normoxic (N) or hypoxic (H, 10% O 2 ) pregnancy ± melatonin (M) treatment (5 μg·ml −1 .day −1 ) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15–20 of gestation (term is ca . 22 days). To control for possible effects of maternal hypoxia‐induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair‐fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in ‐ vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair‐fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch‐up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia‐induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair‐fed pregnancies. Whilst maternal treatment of normoxic or pair‐fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.
Publisher: Wiley
Date: 17-08-2022
DOI: 10.1111/JPI.12821
Abstract: Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6–20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H 2 O 2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain ( p .01) and increased placental weight ( p .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) ( p .05), and an increase in H 2 O 2 production/O 2 consumption ( p .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration ( p .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.
Publisher: Springer New York
Date: 2014
DOI: 10.1007/978-1-4939-1031-1_7
Abstract: The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2023
DOI: 10.1161/HYPERTENSIONAHA.122.19647
Abstract: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.
Publisher: Wiley
Date: 14-03-2012
Publisher: Wiley
Date: 17-04-2019
DOI: 10.1111/JOA.12990
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
DOI: 10.1038/S41390-021-01489-4
Abstract: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1 , hypoxia signaling genes ( HIF-2α , HIF-3α , ADM , and EGLN-3 ), genes regulating sodium movement ( SCNN1-A , SCNN1-B , ATP1-A1 , and ATP1-B1 ), surfactant maturation ( SFTP-B and ABCA3 ), and airway remodeling ( ELN ). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.
Publisher: Wiley
Date: 13-05-2015
DOI: 10.1111/JPI.12242
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00391.2017
Abstract: Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
Publisher: Wiley
Date: 29-02-2016
DOI: 10.1113/JP271091
Publisher: Wiley
Date: 02-03-2018
DOI: 10.1113/JP274340
Publisher: Wiley
Date: 29-02-2016
DOI: 10.1113/JP272000
Publisher: Wiley
Date: 24-03-2019
DOI: 10.1113/JP277431
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.PRRV.2016.08.011
Abstract: Exposure to altered intrauterine conditions during pregnancy influences both fetal growth and organ development. Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction (IUGR) that may influence the risk of infants experiencing respiratory complications at birth. There are a variety of signalling pathways that contribute to normal fetal lung development at the molecular level. The specific molecular effects of chronic hypoxaemia associated with IUGR on lung development are likely to be dependent on the specific aetiology (maternal, placental and/or fetal factors) that can alter hormone concentrations, oxygen and nutrient transport to the fetus. This review discusses molecular pathways that may contribute to altered fetal lung maturation following exposure to chronic hypoxaemia. Importantly, these studies highlight that the heterogeneity in respiratory outcomes at birth in this obstetric subpopulation are likely determined by the timing, severity and duration of chronic hypoxaemia encountered by the fetus during pregnancy.
Publisher: Wiley
Date: 29-04-2018
DOI: 10.1113/JP275659
Publisher: Public Library of Science (PLoS)
Date: 19-08-2015
Publisher: Wiley
Date: 03-2002
DOI: 10.1113/JPHYSIOL.2001.012926
Abstract: In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long-term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low ( 1.52 kg n = 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for approximately 30 min using standard recording equipment and basal arterial blood s les were taken for hormone analyses. Concentrations of angiotensin-converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3-month-old pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3-month-old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.
Publisher: American Physiological Society
Date: 2006
Publisher: Wiley
Date: 19-07-2023
DOI: 10.1113/JP284786
Abstract: Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. However, whether antenatal antioxidant therapy confers any benefit on lung development in complicated pregnancies has not yet been investigated. Here, we tested the hypothesis that maternal antenatal treatment with MitoQ will protect the developing lung in hypoxic pregnancy in sheep, a species with similar fetal lung developmental milestones as humans. Maternal treatment with MitoQ during late gestation promoted fetal pulmonary surfactant maturation and an increase in the expression of lung mitochondrial complexes III and V independent of oxygenation. Maternal treatment with MitoQ in hypoxic pregnancy also increased the expression of genes regulating liquid reabsorption in the fetal lung. These data support the hypothesis tested and suggest that MitoQ as an antenatal targeted antioxidant treatment may improve lung maturation in the late gestation fetus. image Chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. MitoQ is a targeted antioxidant that uses the cell and the mitochondrial membrane potential to accumulate within the mitochondria. Treatment of healthy or hypoxic pregnancy with MitoQ, increases the expression of key molecules involved in surfactant maturation, lung liquid reabsorption and in mitochondrial proteins driving ATP synthesis in the fetal sheep lung. There were no detrimental effects of MitoQ treatment alone on the molecular components measured in the present study, suggesting that maternal antioxidant treatment has no effect on other components of normal maturation of the surfactant system.
Publisher: Elsevier BV
Date: 12-2018
Publisher: The Royal Society
Date: 05-2019
Abstract: High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin–twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposure to HIFU is essential. At 116 ± 2 days gestation, 12 pregnant ewes were assigned to control ( n = 6) or HIFU vascular occlusion ( n = 6) groups and anaesthetized. Placental blood vessels were identified using colour Doppler ultrasound HIFU-mediated vascular occlusion was performed through intact maternal skin (1.66 MHz, 5 s duration, in situ I SPTA 1.8–3.9 kW cm −2 ). Unidentifiable colour Doppler signals in targeted vessels following HIFU exposure denoted successful occlusion. Ewes and fetuses were then surgically instrumented with vascular catheters and transonic flow probes and recovered from anaesthesia. A custom-made wireless data acquisition system, which records continuous maternal and fetal cardiovascular data, and daily blood s ling were used to assess wellbeing for 20 days, followed by post-mortem examination. Based on a comparison of pre- and post-treatment colour Doppler imaging, 100% (36/36) of placental vessels were occluded following HIFU, and occlusion persisted for 20 days. All fetuses survived. No differences in maternal or fetal blood pressure, heart rate, heart rate variability, metabolic status or oxygenation were observed between treatment groups. There was evidence of normal fetal maturation and no evidence of chronic fetal stress. There were no maternal injuries and no placental vascular haemorrhage. There was both a uterine and fetal burn, which did not result in any obstetric or fetal complications. This study demonstrates normal long-term recovery of fetal sheep from exposure to HIFU-mediated placental vascular occlusion and underlines the potential of HIFU as a potential non-invasive therapy in human pregnancy.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-08-2020
Abstract: Mitochondrial therapy may cure hypertension in adult offspring of complicated pregnancies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2022
DOI: 10.1161/HYPERTENSIONAHA.122.19175
Abstract: Preecl sia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preecl sia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology. We adopted an integrative approach to investigate the inter-relationship between chronic hypoxia during pregnancy with maternal, placental, and fetal outcomes, common in preecl sia. We exploited a novel technique using isobaric hypoxic chambers and in vivo continuous cardiovascular recording technology for measurement of blood pressure in sheep and studied the placental stress in response to hypoxia at cellular and subcellular levels. Chronic hypoxia in ovine pregnancy promoted fetal growth restriction (FGR) with evidence of fetal brain-sparing, increased placental hypoxia-mediated oxidative damage, and activated placental stress response pathways. These changes were linked with dilation of the placental endoplasmic reticulum (ER) cisternae and increased placental expression of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), combined with a shift towards an angiogenic imbalance in the maternal circulation. Chronic hypoxia further led to an increase in uteroplacental vascular resistance and the fall in maternal blood pressure with advancing gestation measured in normoxic pregnancy did not occur in hypoxic pregnancy. Therefore, we show in an ovine model of sea-level adverse pregnancy that chronic hypoxia recapitulates physiological and molecular features of preecl sia in the mother, placenta, and offspring.
Publisher: Wiley
Date: 05-06-2020
Publisher: Wiley
Date: 07-05-2017
DOI: 10.1113/JP273842
Publisher: Wiley
Date: 31-07-2015
DOI: 10.1113/JP270995
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Dino Giussani.