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

Abstract

Key pointsr 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 hypoxia 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. 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 and 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.

Models of Intrauterine growth restriction and fetal programming in rabbits

“…It is also a main cause of IUGR at high altitude. Whilst the impact of hypoxia on fetal growth and developmental programming has been widely studied in rodents (Aljunaidy, Morton, Cooke, & Davidge, ; Higgins, Vaughan, Fernandez de Liger, Fowden & Sferruzzi‐Perri, ; Turan, Aberdeen, & Thompson, ) and sheep (Allison et al, ; Herrera et al, ; Parraguez et al, ), few researchers have used the rabbit as an animal model. In pregnant rabbits, continuous exposure to hypobaric oxygen conditions (13.2% oxygen equivalent to 3,657 m) from GD14, decreased fetal and placental weight at GD30–31 (Chang, Rutledge, Stoops, & Abbe, ).…”

“…Hypoxia is a common feature of pathological human pregnancies at sea level and often caused by smoking, anemia, and maternal disease (Giussani, 2016 (Allison et al, 2016;Herrera et al, 2016;Parraguez et al, 2011Parraguez et al, , 2015, few researchers have used the rabbit as an animal model. In pregnant rabbits, continuous exposure to hypobaric oxygen conditions (13.2% oxygen equivalent to 3,657 m) from GD14, decreased fetal and placental weight at GD30-31 (Chang, Rutledge, Stoops, & Abbe, 1984).…”

Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft

“…Herrera et al . () report on cardiovascular function in term fetal sheep conceived, gestated and studied under the influence of chronic hypoxia by exploiting the natural laboratory of the high altitude of the Andean altiplano . Almost ‘keeping it in the family’, again recapitulating many of Barcroft's preoccupations, Allison et al .…”

“…In this issue of The Journal of Physiology, seven papers from laboratories in North and South America, Europe, Australia and New Zealand report on findings using this type of chronically instrumented ovine preparation (Allison et al 2016;Chang et al 2016;Clifton et al 2016;Galinsky et al 2016;Giussani, 2016;Herrera et al 2016;Lear et al 2016). Giussani (2016) reviews the fetal cardiovascular defence to acute hypoxia, highlighting neural, endocrine and vascular redox mechanisms, and introducing the concept of the fetal brain sparing index.…”

“…Giussani (2016) reviews the fetal cardiovascular defence to acute hypoxia, highlighting neural, endocrine and vascular redox mechanisms, and introducing the concept of the fetal brain sparing index. Herrera et al (2016) report on cardiovascular function in term fetal sheep conceived, gestated and studied under the influence of chronic hypoxia by exploiting the natural laboratory of the high altitude of the Andean altiplano. Almost 'keeping it in the family' , again recapitulating many of Barcroft's preoccupations, Allison et al (2016) bring the Andean mountains back to Cambridge.…”