Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus

Abstract

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α 1 -adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.

Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia

“…However, the endocrine data show that this model of early‐onset hypoxic pregnancy was not associated with elevations in glucocorticoids either in the maternal of fetal circulation. This outcome is in keeping with studies of ovine pregnancy at high altitude, 58 and with studies of ovine pregnancy exposed to isobaric chronic hypoxia at sea level 36,59 . It has been proposed that hypoxic pregnancy downregulates adrenocortical sensitivity in fetal life, as an adaptive response to protect against preterm birth induced by chronic hypoxic stress 58 .…”

“…This level of hypoxia simulates ~ 3600 m above sea level, the altitude at which pregnancy complications have been demonstrated to be significantly increased in human populations 6‐8,33‐35 . In experiments in sheep, in which the fetus can be catheterized long term, we have also shown that this level of reduced maternal oxygenation during pregnancy yields fetal arterial PO 2 values between 12 and 14 mmHg 7,36,37 . This is the PO 2 measured by cordocentesis in human fetuses in pregnancy affected by chronic fetal hypoxia 38 .…”

“…This outcome is in keeping with studies of ovine pregnancy at high altitude, 58 and with studies of ovine pregnancy exposed to isobaric chronic hypoxia at sea level. 36,59 It has been proposed that hypoxic pregnancy downregulates adrenocortical sensitivity in fetal life, as an adaptive response to protect against preterm birth induced by chronic hypoxic stress. 58 Therefore, the data in the present study highlight that neurodevelopmental deficits in the adult offspring programmed by early-onset hypoxic pregnancy are not secondary to fetal glucocorticoid over exposure during gestation.…”

“…[6][7][8][33][34][35] In experiments in sheep, in which the fetus can be catheterized long term, we have also shown that this level of reduced maternal oxygenation during pregnancy yields fetal arterial PO 2 values between 12 and 14 mmHg. 7,36,37 This is the PO 2 measured by cordocentesis in human fetuses in pregnancy affected by chronic fetal hypoxia. 38 Uterine wall invasion and the establishment of the placenta commences after day 9.25 of gestation in rat pregnancy, 39 meaning placentation in this model also takes place under hypoxic conditions.…”

Isolating the direct effects of adverse developmental conditions on in vivo cardiovascular function at adulthood: the avian model

“…, 23 Plotting the mean arterial pressure responses to infusion of pressor and depressor drugs against heart rate responses can be used to determine cardiac baroreflex function and investigate autonomic mechanisms in the control of in vivo cardiovascular function 13 20 – 22 , 24 , 25 FVR responses to SNP plotted against the fall in arterial blood pressure further permits determination of vasomotor baroreflex function in vivo 26 . Sustained infusion of SNP over 30 min can also be used to study the cardiovascular response to an acute hypotensive challenge 27 .…”