The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated.
A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction.
The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression.
Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.
Abbreviations used in this paper: BA = basilar artery; E2 = 17β-estradiol benzoate; eNOS = endothelial nitric oxide synthase; ER = estrogen receptor; FoxM1 = Forkhead box; GAPDH = glycer-aldehyde-3-phosphate dehydrogenase; IgG = immunoglobulin G; iNOS = inducible NOS; MPP = methyl-piperidino-pyrazole; NADPH = nicotinamide adenine dinucleotide phosphate; PCR = polymerase chain reaction; ROS = reactive oxygen species; RT = reverse transcription; R,R-THC = R,R-tetrahydrochrysene; SAH = subarachnoid hemorrhage; SD = standard deviation; STAT5 = signal transducer and activator of transcription 5.
Address correspondence to: Shen-Long Howng, M.D., Ph.D., Department of Neurosurgery, Kaohsiung Medical University Hospital, Taiwan, Republic of China. email:
email@example.com, or to Yi-Ren Hong, Ph.D., Graduate Institute of Biochemistry, Kaohsiung Medical University, Taiwan, Republic of China. email:
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