High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep

Abstract

Perinatal exposure to chronic hypoxia induces sustained pulmonary hypertension and structural and functional changes in both pulmonary and systemic vascular beds. The aim of this study was to analyze consequences of high-altitude chronic hypoxia during gestation and early after birth in pulmonary and femoral vascular responses in newborn sheep. Lowland (LLNB; 580 m) and highland (HLNB; 3,600 m) newborn lambs were cathetherized under general anesthesia and submitted to acute sustained or stepwise hypoxic episodes. Contractile and dilator responses of isolated pulmonary and femoral small arteries were analyzed in a wire myograph. Under basal conditions, HLNB had a higher pulmonary arterial pressure (PAP; 20.2 +/- 2.4 vs. 13.6 +/- 0.5 mmHg, P < 0.05) and cardiac output (342 +/- 23 vs. 279 +/- 13 ml x min(-1) x kg(-1), P < 0.05) compared with LLNB. In small pulmonary arteries, HLNB showed greater contractile capacity and higher sensitivity to nitric oxide. In small femoral arteries, HLNB had lower maximal contraction than LLNB with higher maximal response and sensitivity to noradrenaline and phenylephrine. In acute superimposed hypoxia, HLNB reached higher PAP and femoral vascular resistance than LLNB. Graded hypoxia showed that average PAP was always higher in HLNB compared with LLNB at any Po2. Newborn lambs from pregnancies at high altitude have stronger pulmonary vascular responses to acute hypoxia associated with higher arterial contractile status. In addition, systemic vascular response to acute hypoxia is increased in high-altitude newborns, associated with higher arterial adrenergic responses. These responses determined in intrauterine life and early after birth could be adaptive to chronic hypoxia in the Andean altiplano.

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

“…This was a surprise, because chronic hypoxia generally increases pulmonary arterial pressure and depresses pulmonary arterial vasodilatory capacity, as was observed in the newborn (Fig. 2D) and in previous studies (40). The findings suggest that fetal sheep adapt in utero to compensate for eventual birth in a highaltitude, low-O 2 environment.…”

“…2D). This loss could potentially contribute to the elevation in pulmonary pressures and increases in pulmonary vascular resistance that we and others have documented in lambs born at high altitude (10,40). Furthermore, it is possible that the prenatal acceleration of vasorelaxation responses to bradykinin is redistributing blood flow from developing vital organs to the lung, resulting in blood flow distribution issues.…”

Vitamin C Prevents Intrauterine Programming of in vivo Cardiovascular Dysfunction in the Rat

“…However, data in the present study show that in vivo assessment in adult offspring from hypoxic pregnancy provides no evidence of either an increase in peripheral vascular resistance or systemic hypertension. This finding is corroborated by further evidence of no hypertension in highland residents, 40 neonatal sheep from high altitude pregnancy, 35 adult chickens subjected to hypoxia in ovo, 32 or adult rats following prenatal hypoxia. 37, 41 Despite no evidence of any changes in basal arterial blood pressure, this study revealed significant programming on the autonomic control of arterial blood pressure in adult offspring Values are mean ± SEM for baroreflex function in 4-month-old male offspring from Normoxic (N; n=8), Hypoxic (H; n=9), Hypoxic+Vitamin C (HC; n=7) and Normoxic+Vitamin C (NC; n=7) pregnancies.…”

“…8, 29 Secondly, this level of maternal hypoxia induces fetal hypoxia of 10-13 mmHg, 30 which is equivalent to PO2 measured in human umbilical blood taken by cordocentesis in IUGR complicated pregnancies. 31 Several previous studies in many species and at different stages of life, including reports in the chick embryo, 14,32,33 the sheep fetus, 34 the newborn lamb 35 and the adult rat 12,36-39 have consistently shown that exposure to chronic developmental hypoxia leads to increases in sympathetic innervation, greater α1-adrenoreceptor-mediated vasoconstriction and decreased NO-dependent vasodilatation in the peripheral vasculature. Collectively, the data suggest that chronic developmental hypoxia induces a peripheral vasoconstrictor phenotype, which might contribute to a fetal origin of hypertension in later life.…”

Store-operated channels in the pulmonary circulation of high- and low-altitude neonatal lambs

“…Neonatal pulmonary hypertension in humans is associated with developmental chronic hypoxia and results in high mortality, decreased postnatal growth and long lasting neurological, respiratory, and cardiac complications (4,10,14,21,45). We have developed a model of neonatal pulmonary hypertension in sheep, gestated and born at high altitude in the Andean Altiplano, characterized by an increased PAP, impaired vascular reactivity, and altered arterial structure in the pulmonary circulation (14,15,16,18).…”