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Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary.

ABSTRACT: 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.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)-alpha and -beta at the mRNA and protein levels.Both BCO and estradiol treatment were effective in changing ER expression, although the effects were region-specific. BCO dramatically increased ER-alpha in the pituitary and both ER-alpha and ER-beta in the brainstem, while decreasing ER-alpha expression in the hypothalamus. Estradiol treatment decreased ER-alpha expression in the hypothalamus, whereas it increased ER-alpha expression in the brainstem, cerebral cortex and hippocampus.We conclude that the expression of ER-alpha and ER-beta in the brain and pituitary of fetal sheep are influenced by circulating estrogen concentrations and acutely regulated in response to cerebral hypoperfusion.

SUBMITTER: Wood CE

PROVIDER: S-EPMC2793328 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary.

Wood Charles E CE

Neuroendocrinology 20071221 4

<h4>Background/aims</h4>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.<h4>Methods</h4>We s ...[more]

PMID: 18160819

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Project description:Neuroinflammation in utero may result in lifelong neurological disabilities. Astrocytes play a pivotal role in this process, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of astrocytes. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal astrocytes will augment their neuroprotective transcriptome profile, while the inhibition of α7nAChR will achieve the opposite. Using an in vivo-in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep astrocytes cultures re-exposed to LPS in the presence of a selective α7nAChR agonist or antagonist. Our RNAseq findings show that a pro-inflammatory astrocyte transcriptome phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, α7nAChR inhibition potentiates the pro-inflammatory astrocytic transcriptome phenotype. Furthermore, we conducted a secondary transcriptome analysis against the identical α7nAChR experiments in fetal sheep primary microglia cultures. Similar to findings in fetal microglia, in fetal astrocytes we observed a memory effect of in vivo exposure to inflammation, expressed in a perturbation of the iron homeostasis signaling pathway (hemoxygenase 1, HMOX1), which persisted under pre-treatment with α7nAChR antagonist but was reversed with α7nAChR agonist. For both glia cell types, common pathways activated due to LPS included neuroinflammation signaling and NF-κB signaling in some, but not all comparisons. However, overall, the overlap on the level of signaling pathways was rather minimal. Astrocytes, not microglia-the primary immune cells of the brain, were characterized by unique inhibition patterns of STAT3 pathway due to agonistic stimulation of α7nAChR prior to LPS exposure. Lastly, we discuss the implications of our findings for fetal and postnatal brain development.

Dataset Information

Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary.

Publications

Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary.

Similar Datasets

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