Cerebral Hypoperfusion Increases Estrogen Receptor Abundance in the Ovine Fetal Brain and Pituitary

Abstract

Background/Aims: Estrogen is an important component of fetal neuroendocrine function in late-gestation fetal sheep; however, little is known about the regulation of estrogen receptor abundance in the brain and pituitary of fetuses. The present study was performed to test the hypotheses that estrogen receptor abundance in the fetal brain and pituitary are influenced by circulating estradiol concentrations and that they are acutely regulated after cerebral hypoperfusion. Methods: We studied 16 time-dated fetal sheep (124–128 days gestation) that were chronically catheterized and instrumented at least 5 days before study. Four groups (n = 4 each) were studied in which fetuses received estradiol (0.25 mg/day, producing physiological increases in fetal plasma estradiol concentrations) or placebo implants, and in which fetuses received a 10-min period of brachiocephalic occlusion (BCO) or sham-BCO. One hour after BCO or sham-BCO, fetuses were euthanized and tissues rapidly removed for analysis of estrogen receptors (ER)-α and -β at the mRNA and protein levels. Results: Both BCO and estradiol treatment were effective in changing ER expression, although the effects were region-specific. BCO dramatically increased ER-α in the pituitary and both ER-α and ER-β in the brainstem, while decreasing ER-α expression in the hypothalamus. Estradiol treatment decreased ER-α expression in the hypothalamus, whereas it increased ER-α expression in the brainstem, cerebral cortex and hippocampus. Conclusions: We conclude that the expression of ER-α and ER-β in the brain and pituitary of fetal sheep are influenced by circulating estrogen concentrations and acutely regulated in response to cerebral hypoperfusion.

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

“…If this were true, changes in ESR1 abundance would be expected to have an effect on downstream gene expression, but changes in circulating E2 would affect cellular actions through a different mechanism. Downregulation of hypothalamic ESR1 protein in response to chronic E2 administration could at least partially explain the small number of DR genes that are directly E2 sensitive (38). What that mechanism might be is unknown, and it is not possible to discern specific mechanisms from the present study.…”

“…We have also reported that, in these experiments, the E2 treatment reduced ESR1 protein (but not mRNA) in the fetal hypothalamus (38). We do not know the degree of binding of E2 to the ER at prevailing plasma concentrations of E2.…”

“…Disturbances in cerebral blood flow can result from various manipulations in the neonatal intensive care unit, including hypocarbia secondary to mechanical ventilation (18), continuous positive airway pressure (16, 42), and extracorporeal membrane oxygenation (7). Reduction of cerebral blood flow in the neonate compromises oxygen delivery or, if severe, produces ischemia/reperfusion injury (10) and results in morbidity, including intraventricular hemorrhage (6) and long-term cognitive deficit (14).We have investigated the cardiovascular and endocrine responses to cerebral hypoperfusion in late-gestation chronically catheterized fetal sheep (31,38,39), in this animal model of late fetal development. This model allows us to investigate responses to stress in utero and better understand the native homeostatic mechanisms that promote survival after stress.…”

“…We have investigated the cardiovascular and endocrine responses to cerebral hypoperfusion in late-gestation chronically catheterized fetal sheep (31,38,39), in this animal model of late fetal development. This model allows us to investigate responses to stress in utero and better understand the native homeostatic mechanisms that promote survival after stress.…”

Influence of Estradiol and Fetal Stress on Luteinizing Hormone, Follicle-Stimulating Hormone, and Prolactin in Late-Gestation Fetal Sheep

“…This possibility seems feasible to us in light of the apparent dissociation of ACTH and cortisol responses to cerebral hypoperfusion [12] , combined with the possibility that pituitary hormones other than ACTH or pro-opiomelanocortin (POMC) might alter adrenal and placental steroidogenesis [13,14] . We speculated that there might be involvement of the fetal hypothalamic-pituitary-gonadal axis in fetal stress responses because we had previously demonstrated that cerebral hypoperfusion resulted in upregulation of estrogen receptor ␣ in the fetal pituitary and medullary brainstem [15] . We hypothesized that gonadotropins and/or prolactin (PRL) are upregulated in fetal pituitary in response to hypoperfusion stress and that the synthesis of these hormones in both unstressed and stressed fetuses is modulated by estrogen.…”