Role of P450 Aromatase in Sex-Specific Astrocytic Cell Death

Liu, Mingyue; Hurn, Patricia D.; Roselli, Charles E.; Alkayed, Nabil J.

doi:10.1038/sj.jcbfm.9600331

Cited by 134 publications

(125 citation statements)

References 44 publications

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“…Three types of pups were born: wild-type (WT), knockout (ArKO), and heterozygote (HT). In agreement with data generated in sex-specific rat astrocytes (Liu, et al, 2007), we found that female WT mouse astrocytes are more resistant to oxygen-glucose deprivation (OGD) than male WT mouse astrocytes. It is important to note that male sensitivity and female resistance to OGD are observed across species.…”

Section: Discussionsupporting

confidence: 79%

“…We reported that astrocytes isolated from neonatal cortex exhibited marked sex differences in sensitivity to oxygen glucose deprivation (OGD) in part due to higher aromatase expression in female astrocytes compared to male cells. The aromatase inhibitor Arimidex abolished sex differences in OGD-induced cell death (Liu, et al, 2007), suggesting that sex differences in ischemic cell death are related to aromatase expression (Liu, et al, 2007). Such experiments conducted in steroid-free media indicate that some mechanisms of injury (or survival) may be linked to the genetic sex of the cell.…”

Section: Discussionmentioning

confidence: 98%

“…The aromatase inhibitor Arimidex abolished sex differences in OGD-induced cell death (Liu, et al, 2007). In this study, we developed a method to establish an in vitro ischemic model using P450 aromatase-knockout (ArKO) mice generated from heterozygous breeding harems.…”

Section: Introductionmentioning

confidence: 99%

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A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Liu

Oyarzabal

Yang

et al. 2008

Journal of Neuroscience Methods

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Female astrocytes sustain less cell death from oxygen-glucose deprivation (OGD) than male astrocytes. Arimidex, an aromatase inhibitor, abolishes these sex differences. To verify sexdependent differences in P450 aromatase function in astrocyte cell death following OGD, we developed a novel method that uses sex-specific and genotype-specific single pup primary astrocyte cultures from wild-type (WT) and aromatase-knockout (ArKO) mice. After determining sex by external and internal examination as well as PCR and genotype by PCR amplification of tail cDNA, we established cultures from 1−3 day-old male and female, WT and ArKO mice pups and grew them to confluence in estrogen-free media. Cell death was measured by lactate dehydrogenase (LDH) assay. Our study shows that, while WT female astrocytes are more resistant to OGD than WT male cells, sex differences disappear in ArKO cells. Cell death is significantly increased in ArKO compared to WT in female astrocytes but not male cells. Therefore, P450 aromatase appears to be essential in endogenous neuroprotection in females, and this finding may have clinical implications. This innovative technique may also be applied to other in vitro studies of sex-related functional differences.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 98%

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A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Liu

Oyarzabal

Yang

et al. 2008

Journal of Neuroscience Methods

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“…Indeed, endogenous protective processes have been reported in cultured astrocytes from female neonatal mice that are more resistant to injury and cell death than male astrocytes. 33 The finding that MAP-2 expression in the subgranular zone was not affected by gestational age suggests that neuronal proliferation is advanced at the age of preterm delivery used in this study. The possibility that there are long-term neurodevelopmental effects of a deficit in progesterone or allopregnanolone exposure in preterm neonates requires further investigation.…”

Section: Discussionmentioning

confidence: 68%

Changes in Neuroactive Steroid Concentrations After Preterm Delivery in the Guinea Pig

2013

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Background: Preterm birth is a major cause of neurodevelopmental disorders. Allopregnanolone, a key metabolite of progesterone, has neuroprotective and developmental effects in the brain. The objectives of this study were to measure the neuroactive steroid concentrations following preterm delivery in a neonatal guinea pig model and assess the potential for postnatal progesterone replacement therapy to affect neuroactive steroid brain and plasma concentrations in preterm neonates. Methods: Preterm (62-63 days) and term (69 days) guinea pig pups were delivered by cesarean section and tissue was collected at 24 hours. Plasma progesterone, cortisol, allopregnanolone, and brain allopregnanolone concentrations were measured by immunoassay. Brain 5a-reductase (5aR) expression was determined by Western blot. Neurodevelopmental maturity of preterm neonates was assessed by immunohistochemistry staining for myelination, glial cells, and neurons. Results: Brain allopregnanolone concentrations were significantly reduced after birth in both preterm and term neonates. Postnatal progesterone treatment in preterm neonates increased brain and plasma allopregnanolone concentrations. Preterm neonates had reduced myelination, low birth weight, and high mortality compared to term neonates. Brain 5aR expression was also significantly reduced in neonates compared to fetal expression. Conclusions: Delivery results in a loss of neuroactive steroid concentrations resulting in a premature reduction in brain allopregnanolone in preterm neonates. Postnatal progesterone therapy reestablished neuroactive steroid levels in preterm brains, a finding that has implications for postnatal growth following preterm birth that occurs at a time of neurodevelopmental immaturity.

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“…Extragonadal estrogen synthesis by local tissue aromatase becomes the major source of estrogen in postmenopausal women (47,51). Within the brain, aromatase has been localized to multiple cell types, including neurons, astrocytes, smooth muscle cells, and endothelial cells (6,12,16,25,31,48).…”

mentioning

confidence: 99%

Role of aromatase in sex-specific cerebrovascular endothelial function in mice

Zuloaga

Davis

Zhang

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Zuloaga KL, Davis CM, Zhang W, Alkayed NJ. Role of aromatase in sex-specific cerebrovascular endothelial function in mice. Am J Physiol Heart Circ Physiol 306: H929 -H937, 2014. First published February 7, 2014 doi:10.1152/ajpheart.00698.2013.-Stroke risk and outcome are strongly modified by estrogen. In addition to ovaries, estrogen is produced locally in peripheral tissue by the enzyme aromatase, and extragonadal synthesis becomes the major source of estrogen after menopause. Aromatase gene deletion in female mice exacerbates ischemic brain damage after stroke. However, it is not clear which cell type is responsible for this effect, since aromatase is expressed in multiple cell types, including cerebrovascular endothelium. We tested the hypothesis that cerebrovascular aromatase contributes to sex differences in cerebrovascular endothelial function. Cerebrocortical microvascular responses to the endothelium-dependent vasodilator ACh were compared between male and female wild-type (WT) and aromatase knockout (ArKO) mice by measuring laser-Doppler perfusion in vivo through a closed cranial window. Additional studies were performed in WT mice treated with the aromatase inhibitor fadrozole or vehicle. WT female mice had significantly greater responses to ACh compared with WT males (P Ͻ 0.001), which was associated with higher aromatase expression in female compared with male cerebral vessels (P Ͻ 0.05). ACh responses were significantly lower in ArKO compared with WT females (P Ͻ 0.05) and in WT females treated with fadrozole versus vehicle (P Ͻ 0.001). Conversely, ACh responses were significantly higher in ArKO versus WT males (P Ͻ 0.05). Levels of phosphorylated endothelial nitric oxide synthase (eNOS) were lower in ArKO versus WT female brains, but were not altered by aromatase deletion in males. We conclude that cerebrovascular endothelial aromatase plays an important and sexually dimorphic role in cerebrovascular function and that aromatase inhibitors in clinical use may have cardiovascular consequences in both males and females.

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Role of P450 Aromatase in Sex-Specific Astrocytic Cell Death

Cited by 134 publications

References 44 publications

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Changes in Neuroactive Steroid Concentrations After Preterm Delivery in the Guinea Pig

Role of aromatase in sex-specific cerebrovascular endothelial function in mice

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