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

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 ∼90% 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 (∼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 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.

Figure 1. Cardiovascular function in fetal sheep

Mean systemic arterial pressure (MSAP, A) and heart rate (HR, B) and in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Histograms represent 15 min average of the experimental periods (basal, early hypoxia, late hypoxia and recovery). Values are means ± SEM. Significant differences (P ≤ 0.05): a vs. LA and b vs. basal.

Figure 2. Carotid function in fetal sheep

Carotid blood flow (CBF, A) and carotid vascular resistance (CVR, B) in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Histograms represent 15 min average of the experimental periods (basal, early hypoxia, late hypoxia and recovery). Values are means ± SEM. Significant differences (P ≤ 0.05): a vs. LA and b vs. basal.

Figure 3. Femoral function in fetal sheep

Femoral blood flow (FBF, A) and femoral vascular resistance (FVR, B) in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Histograms represent 15 min average of the experimental periods (basal, early hypoxia, late hypoxia and recovery). Values are means ± SEM. Significant differences (P ≤ 0.05): a vs. LA and b vs. basal.

Figure 4. Organ blood flow in fetal sheep

Blood flow to brain (BBF, A), heart (HBF, B), adrenal (ABF, C) and umbilical (UBF, D) vascular beds in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Values are means ± SEM. Significant differences (P ≤ 0.05): a vs. LA and c vs. all periods in the group.

Figure 5. Contractile function in middle cerebral arteries from fetal sheep

Vasoconstrictor response of middle cerebral arteries to potassium chloride (KCl, A), noradrenaline (NA, B), and phenylephrine (Phe, C) in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Values are means ± SEM. Significant differences (P ≤ 0.05): a vs. LA.

Figure 6. Contractile function in femoral arteries from fetal sheep

Vasoconstrictor response of femoral arteries to potassium chloride (KCl, A), noradrenaline (NA, B), and phenylephrine (Phe, C) in low altitude (LA, open circles/bars) and high altitude (HA, filled circles/bars) fetal lambs. Values are means ± SEM. Significant differences (P ≤ 0.05): a vs LA.