Browsing by Autor "Marcelino Gonzales"

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Comparative responses of arterial oxygen saturation and heart rate during postnatal development in rats living at high and low altitude.
(Wiley, 2013) A. Lemoine; Gabriella Villalpando; Marcelino Gonzales; Rudy Soria; Vincent Joseph
We used pulse oximetry to measure arterial oxygen saturation (SpO2) and heart rate (HR) in 4 and 14 day‐old rats raised at HA (La Paz, Bolivia, 3,600 m/12,000ft) or at sea level (SL, Québec, Canada). SpO2 and HR were measured at 5 different levels of inspired PO2 (PiO2: 160 ‐ 60 mmHg – 10 min each), in awake rats maintained in a chamber flushed with room air or the desired gas mixtures. When exposed to a PiO2 of 160 mmHg, P4 HA rats had a similar SpO2 than P4 SL, but a lower HR. At lower PiO2, HA rats maintained a much higher SpO2 than SL rats. HR increased in HA rats (but not in SL rats) at low PiO2. Contrastingly, P14 HA rats exposed to a PiO2 of 160 mmHg had a lower SpO2 than SL (93.7±1.1% vs. 98.8±0.1%, p<0.0001), and similar SpO2 at lower PiO2. HR was higher in P14 HA rats vs. SL rats at all PiO2 levels. A group of SL rats was raised in hypoxia (13.5% O2 – similar to HA PiO2) between P4 and P14. This reduces SpO2 values measured at PiO2 below 160 mmHg, and enhances HR. Male and female rats had similar responses. We conclude that: a) 4‐day old rats raised at HA had efficient responses that help maintaining a high SpO2 under a wide range of PiO2 ‐ b) these responses are no longer apparent in P14. Since rats are not found under natural conditions at HA, success to develop adequate responses to hypoxia during early postnatal development might be critical for genetic adaptation to altitude. Founded by NSERC.
Divergent Mitochondrial Antioxidant Activities and Lung Alveolar Architecture in the Lungs of Rats and Mice at High Altitude
(Frontiers Media, 2018) Alexandra Jochmans‐Lemoine; Susana Revollo; Gabriella Villalpando; I. Valverde; Marcelino Gonzales; Sofien Laouafa; Jorge Soliz; Vincent Joseph
Compared with mice, adult rats living at 3,600 m above sea level (SL-La Paz, Bolivia) have high hematocrit, signs of pulmonary hypertension, and low lung volume with reduced alveolar surface area. This phenotype is associated with chronic mountain sickness in humans living at high altitude (HA). We tested the hypothesis that this phenotype is associated with impaired gas exchange and oxidative stress in the lungs. We used rats and mice (3 months old) living at HA (La Paz) and SL (Quebec City, Canada) to measure arterial oxygen saturation under graded levels of hypoxia (by pulse oximetry), the alveolar surface area in lung slices and the activity of pro- (NADPH and xanthine oxidases-NOX and XO) and anti- (superoxide dismutase, and glutathione peroxidase-SOD and GPx) oxidant enzymes in cytosolic and mitochondrial lung protein extracts. HA rats have a lower arterial oxygen saturation and reduced alveolar surface area compared to HA mice and SL rats. Enzymatic activities (NOX, XO, SOD, and GPx) in the cytosol were similar between HA and SL animals, but SOD and GPx activities in the mitochondria were 2-3 times higher in HA vs. SL rats, and only marginally higher in HA mice vs. SL mice. Furthermore, the maximum activity of cytochrome oxidase-c (COX) measured in mitochondrial lung extracts was also 2 times higher in HA rats compared with SL rats, while there was only a small increase in HA mice vs. SL mice. Interestingly, compared with SL controls, alterations in lung morphology are not observed for young rats at HA (15 days after birth), and enzymatic activities are only slightly altered. These results suggest that rats living at HA have a gradual reduction of their alveolar surface area beyond the postnatal period. We can speculate that the elevation of SOD, GPx, and COX activities in the lung mitochondria are not sufficient to compensate for oxidative stress, leading to damage of the lung tissue in rats.
Divergent physiological responses in laboratory rats and mice raised at high altitude
(The Company of Biologists, 2015) Alexandra Jochmans‐Lemoine; Gabriella Villalpando; Marcelino Gonzales; I. Valverde; Rudy Soria; Vincent Joseph
Ecological studies show that mice can be found at high altitude (HA - up to 4000 m) while rats are absent at these altitudes, and there are no data to explain this discrepancy. We used adult laboratory rats and mice that have been raised for more than 30 generations in La Paz, Bolivia (3600 m), and compared their hematocrit levels, right ventricular hypertrophy (index of pulmonary hypertension) and alveolar surface area in the lungs. We also used whole-body plethysmography, indirect calorimetry and pulse oxymetry to measure ventilation, metabolic rate (O2 consumption and CO2 production), heart rate and pulse oxymetry oxygen saturation (pO2 ,sat) under ambient conditions, and in response to exposure to sea level PO2 (32% O2=160 mmHg for 10 min) and hypoxia (18% and 15% O2=90 and 75 mmHg for 10 min each). The variables used for comparisons between species were corrected for body mass using standard allometric equations, and are termed mass-corrected variables. Under baseline, compared with rats, adult mice had similar levels of pO2 ,sat, but lower hematocrit and hemoglobin levels, reduced right ventricular hypertrophy and higher mass-corrected alveolar surface area, tidal volume and metabolic rate. In response to sea level PO2 and hypoxia, mice and rats had similar changes of ventilation, but metabolic rate decreased much more in hypoxia in mice, while pO2 ,sat remained higher in mice. We conclude that laboratory mice and rats that have been raised at HA for >30 generations have different physiological responses to altitude. These differences might explain the different altitude distribution observed in wild rats and mice.
Elevation of Pulmonary Artery Pressure in Newborns from High-Altitude Pregnancies Complicated by Preeclampsia
(Multidisciplinary Digital Publishing Institute, 2023) Carlos E. Salinas-Salmon; Carla Murillo-Jauregui; Marcelino Gonzales; Vannia Espinoza-Pinto; Silvia V. Mendoza; Rosario Ortega Ruiz; Rodrigo Vargas; Yuri Pérez; Jaime Montaño; Lilian Toledo
We hypothesized that fetal exposure to the oxidative stress induced by the combined challenge of preeclampsia (PE) and high altitude would induce a significant impairment in the development of pulmonary circulation. We conducted a prospective study in La Paz (Bolivia, mean altitude 3625 m) in which newborns from singleton pregnancies with and without PE were compared (PE group n = 69, control n = 70). We conducted an echocardiographic study in these infants at the median age of two days. The percentage of cesarean deliveries and small for gestational age (SGA) infants was significantly higher in the PE group. Heart rate, respiratory rate, and oxygen saturation did not vary significantly between groups. Estimated pulmonary arterial pressure and pulmonary vascular resistance were 30% higher in newborns exposed to PE and high altitude compared with those exposed only to high altitude. We also detected signs of right ventricular hypertrophy in infants subjected to both exposures. In conclusion, this study provides evidence that the combination of PE and pregnancy at high altitude induces subclinical alterations in the pulmonary circulation of the newborn. Follow-up of this cohort may provide us with valuable information on the potential increased susceptibility to developing pulmonary hypertension or other pulmonary and cardiovascular disorders.
Enhanced erythropoietin expression in the brainstem of newborn rats at high altitude
(Elsevier BV, 2011) Tommy Seaborn; Marcelino Gonzales; Gabriela Villalpando; Beat Grenacher; Ruddy Soria; Jorge Soliz
Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: Apnea of prematurity and sex dimorphism
(Elsevier BV, 2019) Sofien Laouafa; Pablo Iturri; Christian Arias‐Reyes; François Marcouiller; Marcelino Gonzales; Vincent Joseph; Aïda Bairam; Jorge Soliz
High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice
(The Company of Biologists, 2025) Maud Demarest; Fernanda Aliaga‐Raduán; Christian Arias‐Reyes; Marcelino Gonzales; Edith M. Schneider Gasser; Jorge Soliz; Vincent Joseph
Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood; however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats, are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex of both species across postnatal development and at adulthood at sea level (SL; Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600 m) after 50 generations of residency. At postnatal day (P)7, P14 and P21 and in adults (P60-90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway - OCRN), complex II (S pathway - OCRS) and complexes I+II (NS pathways - OCRNS). Our results showed: (1) at HA, rats exhibit higher OCR at P7, P14 and adulthood compared with their SL counterparts, and (2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance of studying HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.
Life-long consequences of postnatal normoxia exposure in rats raised at high altitude
(American Physiological Society, 2011) Delphine Lumbroso; A. Lemoine; Marcelino Gonzales; Gabriela Villalpando; Tommy Seaborn; Vincent Joseph
We tested the hypothesis that exposure of high-altitude (HA) rats to a period of postnatal normoxia has long-term consequences on the ventilatory and hematological acclimatization in adults. Male and female HA rats (3,600 m, Po 2 ≃ 100 Torr; La Paz, Bolivia) were exposed to normal room air [HA control (HACont)] or enriched oxygen (32% O 2 ; Po 2 ≃ 160 Torr) from 1 day before to 15 days after birth [HA postnatal normoxia (HApNorm)]. Hematocrit and hemoglobin values were assessed at 2, 12, and 32 wk of age. Cardiac and lung morphology were assessed at 12 wk by measuring right ventricular hypertrophy (pulmonary hypertension index) and lung air space-to-tissue ratio (indicative of alveolarization). Respiratory parameters under baseline conditions and in response to 32% O 2 for 10 min (relieving the ambient hypoxic stimulus) were measured by whole body plethysmography at 12 wk. Finally, we performed a survival analysis up to 600 days of age. Compared with HACont, HApNorm rats had reduced hematocrit and hemoglobin levels at all ages (both sexes); reduced right ventricular hypertrophy (both sexes); lower air space-to-tissue ratio in the lungs (males only); reduced CO 2 production rate, but higher oxygen uptake (males only); and similar respiratory frequency, tidal volume, and minute ventilation. When breathing 32% O 2 , HApNorm male rats had a stronger decrease of minute ventilation than HACont. HApNorm rats had a marked tendency toward longer survival throughout the study. We conclude that exposure to ambient hypoxia during postnatal development in HA rats has deleterious consequences on acclimatization to hypoxia as adults.
Living at high altitude induces a switch from complex I to complex II in hepatic mitochondria of mice during postnatal development
(American Physiological Society, 2025) Maud Demarest; Fernanda Aliaga‐Raduán; Marcelino Gonzales; Edith M. Schneider Gasser; Jorge Soliz; Vincent Joseph
Living at high altitude (HA) requires physiological and metabolic adjustments to sustain adequate homeostasis. Mitochondria play a key role in these adaptation processes as it consumes >85% of cellular O 2 to produce energy. In adults, HA hypoxia can induce structural changes in the electron transport chain (ETC) to optimize the use of O 2 . In newborn, postnatal development at HA results in slower growth rate and delayed development for some important homeostatic functions. While there is evidence that in species adapted to HA O 2 utilization is optimized, potential underlying plasticity of metabolic pathways during postnatal development is unknown. Because we already demonstrated that FVB mice are a good model to study HA adaptation, we used this laboratory strain to evaluate mitochondrial O 2 consumption rates (OCR) of liver samples during postnatal development and at adulthood at sea level (SL - Quebec, Canada) and in animals that have been raised at HA for >50 generations (La Paz, Bolivia, 3600m). Using the high-resolution oxygraph Oroboros O2k, we measured OCR in mice at postnatal day 7 (P7), 14 (P14), 21 (P21) and 60 (adults – P60) under states of maximum capacity (ET) with substrates for complex I (ET N – pyruvate, malate, glutamate), complex II (ET S – succinate), or I + II (maximal OCR - ET NS ). Our results show that ET N was considerably reduced at all ages in HA compared to SL mice (P7, -92%; P14, -86%; P21, -87%). Contrastingly, ET S was 32% higher in HA P21 mice while it was 30% lower in HA adults compared to SL. No difference was found for ET NS during postnatal development, but values were lower in HA adults compared with SL (101 ± 26 vs 167 ± 43 pmol/s*mg). We also calculated the relative contribution of CI and CII to maximal OCR (ET NS ). While CI contribution was substantially lower at all ages in HA mice compared to SL, CII participation was higher at P7 (+41%), P14 (+14%) and P21 (+16%) but was unchanged at adulthood. These results suggest that at HA, a development shift occurs from CI to CII, allowing maximal OCR (ET NS ) to remain unchanged between HA and SL. This shift might be a protective mechanism since the activity of CII is only dependent on the availability of its substrate (succinate), while CI is more sensitive to decreases in intracellular O 2 . This reprogramming was absent in adults; both CI and CII activity decreased at HA compared to SL. These differences highlight the distinct effect of HA hypoxia at different life stages. Funded by NSERC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
NADH-linked mitochondrial respiration in the developing mouse brain is sex-, age- and tissue-dependent
(Elsevier BV, 2019) Christian Arias‐Reyes; Karen Losantos-Ramos; Marcelino Gonzales; Daniela Furrer; Jorge Soliz
Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction
(American Physical Society, 2015) Colleen G. Julian; Marcelino Gonzales; Armando Rodríguez; Diva Bellido; Carlos Salinas Salmón; Anne Ladenburger; Lindsay Reardon; Enrique Vargas; Lorna G. Moore
Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.
Preeclampsia and risk of maternal pulmonary hypertension at high altitude in Bolivia
(Cambridge University Press, 2023) Carlos E. Salinas; Olga Patey; Clara Murillo; Marcelino Gonzales; V. Espinoza; S. Mendoza; R. Ruı́z; Rodrigo Vargas; Yalile Perez; Juan José Montaño Moreno
Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregnancy, women who develop PE are at greater risk of PAH compared to women undergoing healthy highland pregnancies. The study was on 140 women in La Paz, Bolivia (3640m). Women undergoing healthy highland pregnancy were controls (C, n = 70; 29 ± 3.3 years old, mean±SD). Women diagnosed with PE were the experimental group (PE, n = 70, 31 ± 2 years old). Conventional (B- and M-mode, PW Doppler) and modern (pulsed wave tissue Doppler imaging) ultrasound were applied for cardiovascular íííassessment. Spirometry determined maternal lung function. Assessments occurred at 35 ± 4 weeks of pregnancy and 6 ± 0.3 weeks after birth. Relative to highland controls, highland PE women had enlarged right ventricular (RV) and right atrial chamber sizes, greater pulmonary artery dimensions and increased estimated RV contractility, pulmonary artery pressure and pulmonary vascular resistance. Highland PE women had lower values for peripheral oxygen saturation, forced expiratory flow and the bronchial permeability index. Differences remained 6 weeks after birth. Therefore, women who develop PE at high altitude are at greater risk of PAH before and long after birth. Hence, women with a history of PE at high altitude have an increased cardiovascular risk that transcends the systemic circulation to include the pulmonary vascular bed.
Preeclampsia and Risk of Maternal Pulmonary Hypertension at High Altitude in Bolivia
(RELX Group (Netherlands), 2022) Carlos E. Salinas; Olga Patey; Carla Victoria Jara Murillo; Marcelino Gonzales; Vania Espinoza; Silvia Mendoza; Rosario Ruiz; Rodrigo Vargas; Yuri Vázquez Pérez; Jaime Montaño
Prolonged postnatal adaptation and enhanced prevalence of congenital heart diseases due to altitude may contribute to newborn mortality in Bolivia
(Wiley, 2025) Alexandra Heath; Inge von Alvensleben; Jesús Ardiles Spielvogel; Pablo Freudenthal; J. Douglas Trapp; Ivanna Noya; Miguel Gálvez; Fanny Mendizábal; Marcelino Gonzales; Ceylan Apaza
Highland populations suffer from significant infant mortality due to chronic ambient hypoxia, which increases the risk of congenital heart disease (CHD) and neonatal pulmonary hypertension. Neither the prevalence of these conditions nor the effectiveness of neonatal cardiac screening to identify CHD or pulmonary hypertension among neonates born at altitudes >4000 m in Bolivia has been reported. In a study of 1033 newborns in El Alto, Bolivia (4150 m), we determined the prevalence of CHD and prolonged postnatal adaptation. We also tested the accuracy of a neonatal cardiac screening tool in identifying infants with/without these conditions. Finally, diagnoses were contrasted between offspring born to parents of lowland versus highland origin. CHD was found in 54 neonates (5.2%), with the most common diagnoses being patent ductus arteriosus and atrial septal defect. Pulmonary hypertension without CHD was observed in 64 neonates (6.8%), with seven cases of persistent pulmonary hypertension of the newborn (PPHN). The neonatal cardiac screening tool showed a sensitivity of 45% and specificity of 99% for CHD, and 35% sensitivity and 92% specificity for prolonged pulmonary adaptation. Offspring of highland-origin women tended to have increased CHD risk, while those from lower altitudes were predisposed to prolonged postnatal adaptation and PPHN; paternal altitude of origin had no statistic significance but showed same tendency. The high prevalence of relevant CHD and prolonged pulmonary adaptation in neonates born >4000 m in Bolivia likely contributes to the high infant mortality rates observed. The poor sensitivity of the pilot neonatal cardiac screening instrument underscores the need to develop evidence-based tools optimized for use in low-resource, high-altitude settings.
Sleep-disordered breathing and oxidative stress in preclinical chronic mountain sickness (excessive erythrocytosis)
(Elsevier BV, 2013) Colleen G. Julian; Enrique Vargas; Marcelino Gonzales; R. Daniela Dávila; Anne Ladenburger; Lindsay Reardon; Caroline Schoo; Robert W. Powers; Teofilo Lee‐Chiong; Lorna G. Moore
Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy
(Wiley, 2015) Colleen G. Julian; Brent S. Pedersen; Carlos Salinas Salmón; Ivana V. Yang; Marcelino Gonzales; Enrique Vargas; Lorna G. Moore; David A. Schwartz
Epigenomic processes are believed to play a pivotal role for the effect of environmental exposures in early life to modify disease risk throughout the lifespan. Offspring of women with hypertensive complications of pregnancy (HTNPREG ) have an increased risk of developing systemic and pulmonary vascular dysfunction in adulthood. In this preliminary report, we sought to determine whether epigenetic modifications of genes involved in the regulation of vascular function were present in HTNPREG offspring. We contrasted DNA methylation and gene expression patterns of peripheral blood mononuclear cells obtained from young male offspring of HTNPREG (n = 5) to those of normotensive controls (n = 19). In HTNPREG offspring we identified six differentially methylated regions (DMRs) including three genes (SMOC2, ARID1B and CTRHC1) relevant to vascular function. The transcriptional activity of ARID1B and CTRCH1 was inversely related to methylation status. HTNPREG offspring had higher systolic pulmonary artery pressure (sPPA ) versus controls. Our findings demonstrate that epigenetic marks are altered in offspring of HTNPREG with a modest elevation of sPPA and introduce novel epigenomic targets for further study. On the basis of these findings we speculate that epigenomic mechanisms may be involved in mediating the effect of HTNPREG to raise the risk of vascular disease later in life.