Emilio Herrera

Universidad de Chile, Faculty of Medicine, ICBM, Faculty Member

Followers

Following

Co-authors

Public Views

Interests

Uploads

Papers by Emilio Herrera

Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress

Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is ... more 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 path-ophysiological 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.

format_quoteChronic hypoxia and oxidative stress during pregnancy increases perinatal morbidity and contributes to fetal programming of adult diseases.format_quote

Download

Cardiovascular function in term fetal sheep conceived, gestated and studied in the hypobaric hypoxia of the Andean altiplano

Key points r High altitude developmental hypoxia causes intrauterine growth restriction and cardi... more Key points r High altitude developmental hypoxia causes intrauterine growth restriction and cardiovascular programming. However, some mammals exposed chronically to high-altitude hypoxia have less growth restriction suggesting certain protection. r Cardiovascular defence mechanisms during acute fetal hypoxia divert blood flow from the periphery towards the brain, heart and adrenals. In contrast, little is known about the cardiovascular defence mechanisms during chronic fetal hypoxia. r Here, we established the cardiovascular responses in fetal sheep that were conceived, gestated, born and studied at 3600 m. The data suggest that chronically hypoxic pregnant ewes and their fetuses have evolved different mechanisms from sea level pregnancies to withstand chronic hypoxia. r The cardiovascular responses to acute hypoxia are blunted in the chronically hypoxic fetus. These findings points towards compensatory mechanisms in the highland fetus at the level of the cells and molecules rather than mounting major cardiovascular responses, saving oxygen not easily available in the Alto Andino. Abstract High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. However, adult humans and animals that have evolved at altitude show certain protection against the effects of chronic hypoxia. Whether the highland fetus shows similar protection against high altitude gestation is unclear. We tested the hypothesis that high-altitude fetal sheep have evolved cardiovascular compensatory mechanisms to withstand chronic hypo-xia that are different from lowland sheep. We studied seven high-altitude (HA; 3600 m) and eight low-altitude (LA; 520 m) pregnant sheep at ß90% gestation. Pregnant ewes and fetuses were instrumented for cardiovascular investigation. A three-period experimental protocol was performed in vivo: 30 min of basal, 1 h of acute superimposed hypoxia (ß10% O 2) and 30 min of recovery. Further, we determined ex vivo fetal cerebral and femoral arterial function. HA pregnancy led to chronic fetal hypoxia, growth restriction and altered cardiovascular function. During acute superimposed hypoxia, LA fetuses redistributed blood flow favouring the brain, heart and adrenals, whereas HA fetuses showed a blunted cardiovascular response. Importantly, HA fetuses have a marked reduction in umbilical blood flow versus LA. Isolated cerebral E. A. Herrera and R. T. Rojas contributed equally to this work.

format_quoteHA fetal lambs had a 26% lower weight than LA counterparts, indicating intrauterine growth restriction linked to altitude-related adaptations.format_quote

Download

Fetal in vivo continuous cardiovascular function during chronic hypoxia

Key points r The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and larg... more Key points r The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing. r We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth-restricted fetus. r This technology permits wireless recording in free-moving animals of longitudinal maternal and fetal cardiovascular function, including beat-to-beat alterations in pressure and blood flow signals in regional circulations. r The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism. Abstract Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O 2) hypoxia, yielding fetal mean P aO 2 levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (: 4.8 ± 1.6 vs. 0.5 ± 1.4 μmol l −1 , P<0.05). The data support the hypotheses tested and show persisting redistribution C

Download

Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

Key points r Intrauterine growth restriction (IUGR) is associated with short-and long-term detrim... more Key points r Intrauterine growth restriction (IUGR) is associated with short-and long-term detrimental cardiometabolic effects. r Mice and rats are commonly used to assess IUGR, but differences in placental and fetal developmental physiology relative to those in humans highlight the need for alternative small animal IUGR models. r We developed a guinea pig IUGR model by gradual occlusion of uterine arteries by ameroid constrictor implantation. In this model, reduced uterine blood flow was associated with IUGR, allowing in vivo assessment of fetal growth trajectory and umbilico-placental vascular function in conscious animals. r The intervention induces placental vascular dysfunction and remodelling, as well as altered fetal abdominal growth resulting in an asymmetric IUGR and preserved brain growth. Abstract Intra-uterine growth restriction (IUGR) is associated with short and long-term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid-gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid-gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day −1) compared to control (0.241 cm day −1 , P < 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P < 0.01). These effects were associated with a decrease in the relative luminal area of placental chorionic arteries (21.3 ± 2.2% vs. 33.2 ± 2.7%, P < 0.01) in IUGR sows at near term. Uterine artery intervention reduced fetal (ß30%), placental (ß20%) and liver (ß50%) weights (P < 0.05), with an increased brain to E. A. Herrera and R. Alegría are joint first authors C

Download

Potential adverse effects of antenatal melatonin as a treatment for intrauterine growth restriction: findings in pregnant sheep

BACKGROUND: Intrauterine growth restriction is a condition in which the fetus has a birthweight a... more BACKGROUND: 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. OBJECTIVES: 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. STUDY DESIGN: High-altitude pregnant sheep received either vehicle (n ¼ 5; 5 mL 1.4% ethanol) or melatonin (n ¼ 7; 10 mg/kg e1 day e1 in

Download

Modelling and numerical simulation of the in vivo mechanical response of the ascending aortic aneurysm in Marfan syndrome

personal use only and shall not be self-archived in electronic repositories. If you wish to selfa... more personal use only and shall not be self-archived in electronic repositories. If you wish to selfarchive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

format_quoteMFS tissue exhibits isotropic behavior, significantly deviating in strength from unaffected tissue in stress-stretch ranges.format_quote

Download

Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

by Emilio Herrera, German Ebensperger, and Marcela Diaz

—Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in n... more —Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to pulmonary hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg·kg 1 ·day 1 iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1 T850 and pMYPT1T 696 than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the pulmonary hypertension of the neonates. Rho kinase; hypoxia; pulmonary hypertension; newborn; high altitude EXPOSURE to chronic hypoxia causes pulmonary arterial hyper-tension (PAH), characterized by a progressive elevation of pulmonary artery pressure and resistance, associated with va-soconstriction and vascular remodeling (14, 43). Although PAH can develop at any stage during an individual's lifetime, neonates are especially vulnerable to this syndrome due to the marked changes that take place in the pulmonary circulation at this period of life. At birth, there is a rapid transition from a high resistance-low flow pulmonary circulation in the fetus to a very low resistance condition in the newborn capable of accommodating the total cardiac output (1, 2). Exposure to chronic hypoxia in utero, as seen in some complicated pregnancies at low altitude and in high altitude populations, may lead to persistent pulmonary hypertension of the newborn (37). This is a life-threatening syndrome with a prevalence from 0.43 to 6.82 per 1,000 live births in lowlands (52), and some authors suggested that at high altitude this prevalence is higher than in lowlands (37, 40). Despite the available therapeutic strategies, a high percentage of patients are refractory to these treatments and the mortality rate ranges from 4 to 33%, accompanied by significant morbidity (45, 52). The mechanisms of chronic hypoxia inducing PAH are complex and not completely understood, but the involvement of the RhoA/Rho-kinase (ROCK) pathway has been demonstrated in the rat and mouse, contributing to vascular remod-eling and vasoconstriction through Ca 2 sensitization (38, 54). Thus, ROCK-specific pharmacological inhibitors, fasudil and Y-27632, have been shown to inhibit adult and fetal hypoxic pulmonary artery myogenic responses (9, 51), reversing hy-poxic pulmonary vasoconstriction (12). Furthermore, treatment with ROCK inhibitors suppresses the development of hypoxic PAH in adult rodents (12, 35). ROCKs are cytoplasmic serine/threonine kinases translo-cated to the membrane after activation of the small GTPase RhoA (26). The binding of active RhoA to ROCK RBD (RhoA binding domain) stimulates the phosphotransferase activity of ROCKs (4, 30). Once activated in the smooth muscle, ROCK acts on the regulatory subunit of myosin light chain phospha-tase MYPT1 and phosphorylates MYPT1's threonine 850 and 696. This results in a decreased myosin light chain phosphatase (MLCP) activity and increased levels of phosphorylated myo-sin light chain (MLC) at a constant cytosolic Ca 2 concentration , a mechanism known as Ca 2 sensitization (48, 50). There are two ROCK isoforms, ROCKI and ROCKII, and both are expressed in vascular smooth muscle cells (VSMC) and phos-phorylate MLCP (36). Nevertheless, these proteins seem to

format_quoteFasudil effectively reduced mRNA expression related to the RhoA/ROCK pathway in PASMCs, thus potentially ameliorating pulmonary hypertension in treated neonates.format_quote

Download

Carbon monoxide: a novel pulmonary artery vasodilator in neonatal llamas of the Andean altiplano

by German Ebensperger, Victor Pulgar, Emilio Herrera, and Dino Giussani

Aims To study the nitric oxide (NO) and carbon monoxide roles in the regulation of the pulmonary ... more Aims To study the nitric oxide (NO) and carbon monoxide roles in the regulation of the pulmonary circulation in lowland and highland newborn sheep and llamas. Methods and results We used neonatal sheep (Ovis aries) and llamas (Lama glama) whose gestation and delivery took place at low (580 m) or high (3600 m) altitude. In vivo, we measured the cardiopulmonary function basally and with a NO synthase (NOS) blockade and calculated the production of carbon monoxide by the lung. In vitro, we determined NOS and soluble guanylate cyclase (sGC) expression, NOS activity, and haemoxygenase (HO) expression in the lung. Pulmonary arterial pressure was elevated at high altitude in sheep but not in llamas. Sheep at high altitude relative to sea level had significantly greater total lung NOS activity and eNOS protein, but reduced sGC and HO expression and carbon monoxide production. In contrast, llamas showed no difference in NO function between altitudes, but a pronounced increase in pulmonary carbon monoxide production and HO expression at high altitude. Conclusions In the llama, enhanced pulmonary carbon monoxide, rather than NO, protects against pulmonary hypertension in the newborn period at high altitude. This shift in pulmonary dilator strategy from NO to carbon monoxide has not been previously described, and it may give insight into new treatments for excessive pulmonary vasoconstriction.

format_quoteThe shift from nitric oxide to carbon monoxide as a pulmonary vasodilator may inform new treatment approaches for pulmonary vasoconstriction.format_quote

Download

Carbon monoxide: a novel pulmonary artery vasodilator in neonatal llamas of the Andean altiplano

by German Ebensperger, Dino Giussani, and Emilio Herrera

Cardiovascular Research, 2007

Download

Evolving in thin air—Lessons from the llama fetus in the altiplano

by German Ebensperger, Dino Giussani, and Emilio Herrera

Respiratory Physiology & Neurobiology, 2007

Compared with lowland species, fetal life for mammalian species whose mothers live in high altitu... more Compared with lowland species, fetal life for mammalian species whose mothers live in high altitude is demanding. For instance, fetal llamas have to cope with the low fetal arterial PO2PO2 of all species, but also the likely superimposition of hypoxia as a result of the decreased oxygen environment in which the mother lives in the Andean altiplano. When subjected to acute hypoxia the llama fetus responds with an intense peripheral vasoconstriction mediated by alpha-adrenergic mechanisms plus high plasma concentrations of catecholamines and neuropeptide Y (NPY). Endothelial factors such as NO and endothelin-1 also play a role in the regulation of local blood flows. Unlike fetuses of lowland species such as the sheep, the llama fetus shows a profound cerebral hypometabolic response to hypoxia, decreasing cerebral oxygen consumption, Na–K-ATPase activity and temperature, and resulting in an absence of seizures and apoptosis in neural cells. These strategies may have evolved to prevent hypoxic injury to the brain or other organs in the face of the persistent hypobaric hypoxia of life in the Andean altiplano.

Download

Downregulation of Cystathionine gamma-Lyase (CSE) in Pre-Eclampsia in Placentas with Abnormal Umbilical Artery Doppler Waveforms and Its Potential Regulation by microRNA-21

Reproductive Sciences

Statins Prevent Detrimental Effects of Postnatal Glucocorticoid Therapy on Arterial Blood Pressure and the Kidney in Rats

Reproductive Sciences

Maternal Melatonin: Effective Intervention Against Developmental Programming of Cardiovascular Dysfunction in Adult Offspring of Complicated Pregnancy

Reproductive Sciences

Cardiovascular function in term fetal sheep conceived, gestated and studied in the hypobaric hypoxia of the Andean altiplano

The Journal of Physiology, 2015

High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. Howe... more High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. However, adult humans and animals that have evolved at altitude show certain protection against the effects of chronic hypoxia. Whether the highland fetus shows similar protection against high altitude gestation is unclear. We tested the hypothesis that high-altitude fetal sheep have evolved cardiovascular compensatory mechanisms to withstand chronic hypoxia that are different from lowland sheep. We studied 7 high-altitude (HA: 3,600 m) and 8 low-altitude (LA: 520 m) pregnant sheep at ∼90% gestation. Pregnant ewes and fetuses were instrumented for cardiovascular investigation. A 3-period experimental protocol was performed in vivo: 30 min of basal, 1hour of acute superimposed hypoxia (∼10% O2 ) and 30 min of recovery. Further, we determined ex vivo fetal cerebral and femoral arterial function. HA pregnancy led to chronic fetal hypoxia, growth restriction and altered cardiovascular function. During acute superimposed hypoxia, LA fetuses redistributed blood flow favouring the brain, heart and adrenals, whereas HA fetuses showed a blunted cardiovascular response. Importantly, HA fetuses have a marked reduction in umbilical blood flow versus LA. Isolated cerebral arteries from HA fetuses showed a higher contractile capacity but a diminished response to catecholamines. In contrast, femoral arteries from HA fetuses showed decreased contractile capacity whilst increased adrenergic contractility. The blunting of the cardiovascular responses to hypoxia in fetuses raised in the Alto Andino may indicate a change in control strategy triggered by chronic hypoxia, switching towards compensatory mechanisms that are more cost-effective in terms of oxygen uptake. This article is protected by copyright. All rights reserved.

Melatonin modulates the fetal cardiovascular defense response to acute hypoxia

by Emilio Herrera and Dino Giussani

Journal of pineal research, 2015

Experimental studies in animal models supporting protective effects on the fetus of melatonin in ... more Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in v...

Intrauterine growth restriction in Guinea pig impairs umbilical and systemic vascular function

Placenta, 2015

Objective: Eighty percent of unexplained infertility is associated with an immunological disbalan... more Objective: Eighty percent of unexplained infertility is associated with an immunological disbalance. Among immunological factors, autoantibodies are present many years before the diagnosis of autoimmune diseases in asymptomatic reproductive failure women. In this sense, a new entity called reproductive autoimmune failure syndrome has been described in the last years. On the other hand, increased blood NK cell counts and activity are associated with recurrent abortion and implantation failure. IVIG is able to decrease NK-cell counts and activity and has been suggested as the most effective therapeutic solution for women with increased blood NK cells and infertility. Characterization of endometrial NK cells in these women has not been described yet. Methods: Women with reproductive failure were tested for antithyroglobulin, antithyroid peroxidase, anticardiolipin, antiparietal cell antibody, anti-beta 2 glycoprotein 1 and anti-nuclear antibodies. Endometrial vocal doppler and biopsies were performed and blood samples were obtained during the implantation window. Peripheral NK cells, endometrial NK cells and B1 lymphocytes were counted by flow cytometry. Statistical analysis was performed by Student or Mann Withney and correlations by Pearson test.

Download

Heart Disease Link to Fetal Hypoxia and Oxidative Stress

Advances in Experimental Medicine and Biology, 2014

The quality of the intrauterine environment interacts with our genetic makeup to shape the risk o... more 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.

Foetal and umbilical vascular reactivity in a model of IUGR through gradual uterine artery occlusion in guinea pigs

Placenta, 2014

Evolving in thin air—Lessons from the llama fetus in the altiplano

by Dino Giussani, Emilio Herrera, and Victor Pulgar

Respiratory Physiology & Neurobiology, 2007

Compared with lowland species, fetal life for mammalian species whose mothers live in high altitu... more Compared with lowland species, fetal life for mammalian species whose mothers live in high altitude is demanding. For instance, fetal llamas have to cope with the low fetal arterial P O 2 of all species, but also the likely superimposition of hypoxia as a result of the decreased oxygen environment in which the mother lives in the Andean altiplano. When subjected to acute hypoxia the llama fetus responds with an intense peripheral vasoconstriction mediated by alpha-adrenergic mechanisms plus high plasma concentrations of catecholamines and neuropeptide Y (NPY). Endothelial factors such as NO and endothelin-1 also play a role in the regulation of local blood flows. Unlike fetuses of lowland species such as the sheep, the llama fetus shows a profound cerebral hypometabolic response to hypoxia, decreasing cerebral oxygen consumption, Na-K-ATPase activity and temperature, and resulting in an absence of seizures and apoptosis in neural cells. These strategies may have evolved to prevent hypoxic injury to the brain or other organs in the face of the persistent hypobaric hypoxia of life in the Andean altiplano.

Download

Implications of Dietary Fatty Acids During Pregnancy on Placental, Fetal and Postnatal Development—A Review

Placenta, 2002

During pregnancy, the mother adapts her metabolism to support the continuous draining of substrat... more During pregnancy, the mother adapts her metabolism to support the continuous draining of substrates by the fetus. Her increase in net body weight (free of the conceptus) corresponds to the accumulation of fat depots during the first two-thirds of gestation, switching to an accelerated breakdown of these during the last trimester. Under fasting conditions, adipose tissue lipolytic activity is highly enhanced, and its products, free fatty acids (FFA) and glycerol, are mainly driven to maternal liver, where FFA are converted to ketone bodies and glycerol to glucose, which easily cross the placenta and sustain fetal metabolism. Lipolytic products reaching maternal liver are also used for triglyceride synthesis that are released in turn to the circulation, where together with an enhanced transfer of triglycerides among the different lipoprotein fractions, and a decrease in extrahepatic lipoprotein lipase activity, increase the content of triglycerides in all the lipoprotein fractions. Long chain polyunsaturated fatty acids (LCPUFA) circulate in maternal plasma associated to lipoprotein triglycerides, and in a minor proportion in the form of FFA. Despite the lack of a direct placental transfer of triglycerides, diffusion of their fatty acids to the fetus is ensured by means of lipoprotein receptors, lipoprotein lipase activity and intracellular lipase activities in the placenta. Maternal plasma FFA are also an important source of LCPUFA to the fetus, and their placental uptake occurs via a selective process of facilitated membrane translocation involving a plasma membrane fatty acid-binding protein. This mechanism together with a selective cellular metabolism determine the actual rate of placental transfer and its selectivity, resulting even in an enrichment of certain LCPUFA in fetal circulation as compared to maternal. The degree to which the fetus is capable of fatty acid desaturation and elongation is not clear, although both term and preterm infants can synthesize LCPUFA from parental essential fatty acids. Nutritional status of the mother during gestation is related to fetal growth, and excessive dietary intake of certain LCPUFA has inhibitory effects on Delta-5- and Delta-6-desaturases. This inhibition causes major declines in arachidonic acid levels, as directly found in pregnant and lactating rats fed a fish oil-rich diet as compared to olive oil. An excess in dietary PUFA may also enhance peroxidation and reduce antioxidant capacity. Thus, since benefit to risks of modifying maternal fat intake in pregnancy and lactation are not yet completely established, additional studies are needed before recommendations to increase LCPUFA intake in pregnancy are made.

Emilio Herrera

Uploads

Papers by Emilio Herrera

Log In