ORCID Profile
0000-0002-6342-085X
Current Organisations
Institutional Animal Care and Use Committee - Universidad de Chile
,
University of Cambridge
,
International Center for Andean Studies (INCAS)
,
Universidad Austral de Chile
,
UNIVERSIDAD DE CHILE
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Publications
Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy
Publisher: Wiley
Date: 13-12-2013
Induction of controlled hypoxic pregnancy in large mammalian species
Publisher: Wiley
Date: 12-2015
DOI: 10.14814/PHY2.12614
Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy
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.
Heart Disease Link to Fetal Hypoxia and Oxidative Stress
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.
Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic
Publisher: Wiley
Date: 30-05-2018
DOI: 10.1113/JP274948
Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth
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.
A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep
Publisher: Wiley
Date: 14-03-2012
Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation
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.
Potential adverse effects of antenatal melatonin as a treatment for intrauterine growth restriction: findings in pregnant sheep
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.AJOG.2016.02.040
Abstract: Intrauterine growth restriction is a condition in which the fetus has a birthweight and/or length <10th percentile for the gestational age. Intrauterine growth restriction can be associated with various causes, among which is low uteroplacental perfusion and chronic hypoxia during gestation. Often, intrauterine growth-restricted fetuses have increased oxidative stress therefore, agents that decrease oxidative stress and increase utero, placental, and umbilical perfusion have been proposed as a beneficial therapeutic strategy. In this scenario, melatonin acts as an umbilical vasodilator and a potent antioxidant that has not been evaluated in pregnancies under chronic hypoxia that induce fetal growth restriction. However, this neurohormone has been proposed as a pharmacologic therapy for complicated pregnancies. The aim of this study was to determine the effects of prenatal administration of melatonin during the last trimester of pregnancy on the biometry of the growth-restricted lambs because of developmental hypoxia. Further, we aimed to determine melatonin and cortisol levels and oxidative stress markers in plasma of pregnant ewes during the treatment. High-altitude pregnant sheep received either vehicle (n = 5 5 mL 1.4% ethanol) or melatonin (n = 7 10 mg/kg(-1)day(-1) in 5 mL 1.4% ethanol) daily during the last one-third of gestation. Maternal plasma levels of melatonin, cortisol, antioxidant capacity, and oxidative stress were determined along treatment. At birth, neonates were examined, weighed, and measured (biparietal diameter, abdominal diameter, and crown-rump length). Antenatal treatment with melatonin markedly decreased neonatal biometry and weight at birth. Additionally, melatonin treatment increased the length of gestation by 7.5% and shifted the time of delivery. Furthermore, the prenatal treatment doubled plasma levels of melatonin and cortisol and significantly improved the antioxidant capacity of the pregnant ewes. Our findings indicate that antenatal melatonin induces further intrauterine growth restriction but improves the maternal plasma antioxidant capacity. Additional studies should address the efficiency and safety of antenatal melatonin before clinical attempts on humans.
Melatonin modulates the fetal cardiovascular defense response to acute hypoxia
Publisher: Wiley
Date: 13-05-2015
DOI: 10.1111/JPI.12242
Improving pregnancy outcomes in humans through studies in sheep.
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.
Fetal in vivo continuous cardiovascular function during chronic hypoxia
Publisher: Wiley
Date: 29-02-2016
DOI: 10.1113/JP271091
The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs
Publisher: Frontiers Media SA
Date: 10-01-2022
DOI: 10.3389/FPHYS.2021.765281
Abstract: Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg –1 ] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.
Mechanisms of Cardiovascular Protection Associated with Intermittent Hypobaric Hypoxia Exposure in a Rat Model: Role of Oxidative Stress
Publisher: MDPI AG
Date: 26-01-2018
DOI: 10.3390/IJMS19020366
The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas
Publisher: Wiley
Date: 02-03-2018
DOI: 10.1113/JP274340
Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep
Publisher: Elsevier BV
Date: 04-2019
Quercetin Prevents Diastolic Dysfunction Induced by a High-Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats
Publisher: Hindawi Limited
Date: 2018
DOI: 10.1155/2018/7239123
Abstract: Alterations in cardiac energy metabolism play a key role in the pathogenesis of diabetic cardiomyopathy. Hypercholesterolemia associated with bioenergetic impairment and oxidative stress has not been well characterized in the cardiac function under glycemic control deficiency conditions. This work aimed to determine the cardioprotective effects of quercetin (QUE) against the damage induced by a high-cholesterol (HC) diet in hyperglycemic rats, addressing intracellular antioxidant mechanisms and bioenergetics. Quercetin reduced HC-induced alterations in the lipid profile and glycemia in rats. In addition, QUE attenuated cardiac diastolic dysfunction (increased E:A ratio), prevented cardiac cholesterol accumulation, and reduced the increase in HC-induced myocyte density. Moreover, QUE reduced HC-induced oxidative stress by preventing the decrease in GSH/GSSG ratio, Nrf2 nuclear translocation, HO-1 expression, and antioxidant enzymatic activity. Quercetin also counteracted HC-induced bioenergetic impairment, preventing a reduction in ATP levels and alterations in PGC-1 α , UCP2, and PPAR γ expression. In conclusion, the mechanisms that support the cardioprotective effect of QUE in rats with HC might be mediated by the upregulation of antioxidant mechanisms and improved bioenergetics on the heart. Targeting bioenergetics with QUE can be used as a pharmacological approach to modulate structural and functional changes of the heart under hypercholesterolemic and hyperglycemic conditions.
Ω3 Supplementation and Intermittent Hypobaric Hypoxia Induce Cardioprotection Enhancing Antioxidant Mechanisms in Adult Rats
Publisher: MDPI AG
Date: 04-02-2015
DOI: 10.3390/MD13020838
Progressive uterine artery occlusion in the Guinea pig leads to defects in placental structure that relate to fetal growth
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.PLACENTA.2018.10.003
Abstract: Intrauterine growth restriction (IUGR) is a common obstetric complication with immediate and life-long consequences for offspring health. Yet the mechanisms underlying its aetiology require elucidation. Recent work in the guinea pig shows that progressive uterine artery occlusion induced IUGR and vascular dysfunction in pups. Here we explore the extent to which uterine artery occlusion influences fetal outcomes via impacts on placental morphology. Our study demonstrates that uterine artery occlusion severely compromised both the labyrinth exchange zone (increased fibrosis and reduced vascularisation, trophoblast volume, surface area and diffusing capacity) and interlobium zone (increased apoptosis), which likely contributed to the IUGR observed.
Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PHARMTHERA.2015.11.006
Abstract: Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies.
Developmental Ultrasound Characteristics in Guinea Pigs: Similarities with Human Pregnancy
Publisher: MDPI AG
Date: 10-02-2023
Abstract: Background: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. Methods: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. Results: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. Conclusions: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy.
Analysis of the passive biomechanical behavior of a sheep-specific aortic artery in pulsatile flow conditions
Publisher: Informa UK Limited
Date: 21-01-2021
2-Aminoethyldiphenylborinate modifies the pulmonary circulation in pulmonary hypertensive newborn lambs partially gestated at high altitude
Publisher: American Physiological Society
Date: 10-2016
DOI: 10.1152/AJPLUNG.00230.2016
Abstract: Calcium signaling through store-operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, six of them received a 2-APB treatment and the other six received vehicle treatment for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure between the 3rd and 10th days, cardiac output between the 4th and 8th days, and pulmonary vascular resistance at the 10th day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil, respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin, and the percentage of Ki67-positive nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses, and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension however, further testing of specific blockers is needed.
Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation
Publisher: Wiley
Date: 07-05-2017
DOI: 10.1113/JP273842
Assessment ofin vivofetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs
Publisher: Wiley
Date: 02-02-2016
DOI: 10.1113/JP271467
Related Organisations
Institutional Animal Care And Use Committee - Universidad De Chile
Location: Chile
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Emilio A Herrera.