Estrogen-receptor-mediated protection of cerebral endothelial cell viability and mitochondrial function after ischemic insult in vitro.
Protective effects of estrogen against experimental stroke and neuronal ischemic insult are well-documented, but it is not known whether estrogen prevents ischemic injury to brain endothelium, a key component of the neurovascular unit. Increasing evidence indicates that estrogen exerts protective effects through mitochondrial mechanisms. We previously found 17beta-estradiol (E2) to improve mitochondrial efficiency and reduce mitochondrial superoxide in brain blood vessels and endothelial cells. Thus we hypothesized E2 will preserve mitochondrial function and protect brain endothelial cells against ischemic damage. To test this, an in vitro ischemic model, oxygen-glucose deprivation (OGD)/reperfusion, was applied to immortalized mouse brain endothelial cells (bEnd.3). OGD/reperfusion-induced cell death was prevented by long-term (24, 48 h), but not short-term (0.5, 12 h), pretreatment with 10 nmol/L E2. Protective effects of E2 on endothelial cell viability were mimicked by an estrogen-receptor (ER) agonist selective for ERalpha (PPT), but not by one selective for ERbeta (DPN). In addition, E2 significantly decreased mitochondrial superoxide and preserved mitochondrial membrane potential and ATP levels in early stages of OGD/reperfusion. All of the E2 effects were blocked by the ER antagonist, ICI-182,780. These findings indicate that E2 can preserve endothelial mitochondrial function and provide protection against ischemic injury through ER-mediated mechanisms.
State Key Laboratory of Natural Biomimetic Drugs, Peking University and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
Jiabin
J
Guo
Diana N
DN
Krause
James
J
Horne
John H
JH
Weiss
Xuejun
X
Li
Sue P
SP
Duckles
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D002534:Hypoxia, Brain / Q000473:pathology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
D004967:Estrogens; D011960:Receptors, Estrogen; D013481:Superoxides; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005947:Glucose