Abstract
By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.
Highlights
Hypoxia represents a major threat to the developing fetus and often accompanies situations of preeclampsia, preterm labor, smoking, and high altitude
Since hypoxia is a potent activator of the fetal HPA axis, we initially explored the effect of long-term hypoxia (LTH) on the systemic endocrine HPA response by quantifying basal immunoreactive (IR) ACTH and cortisol concentrations in fetal plasma as well as the response of LTH fetal sheep to an acute secondary stressor during the later stages of gestation [14, 16, 18]
Endothelial NO synthases (NOSs) is the predominant NOS isoform in the ovine fetal adrenal cortex, and more importantly, we demonstrated that LTH increases eNOS mRNA and protein expression [43] and that the increased expression was primarily in CYP17 expressing cells within the zona fasciculata indicating a selective increase in the cortisol producing adrenocortical layer
Summary
Hypoxia represents a major threat to the developing fetus and often accompanies situations of preeclampsia, preterm labor, smoking, and high altitude. More prolonged fetal hypoxemia can be initiated by repeated umbilical cord compression [7,8,9], as well as placental embolization [10, 11] and restriction of uterine blood flow [12] These methods induce either a rather pure hypoxic episode or hypoxia accompanied with acidemia or hypoglycemia. Our model of long-term hypoxia (LTH) uses pregnant ewes maintained at high altitude (3,820 m, Barcroft Laboratory White Mountain Research Station, Bishop, CA) from approximately 40 days’ gestational age onward resulting in a maintained fetal PO2 of ∼18 mmHg (normal ∼23– 25 mmHg) resulting in a moderate state of continuous hypoxia [14,15,16] Under these conditions, fetal hypoxia is achieved without accompanying acidosis, the pregnancies are of normal duration, and the fetuses do not exhibit growth restriction [15, 17]. During our studies on these components of the stress response, we have initiated studies into how LTH impacts development of the fetal perirenal adipose tissue and interactions between this tissue and the HPA axis
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