Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats.
OBJECTIVE
Epidemiological data indicate a high incidence of cerebral aneurysms in postmenopausal women. To elucidate the pathogenesis of cerebral aneurysms, we focused on the contribution of endothelial damage in rats.


METHODS
We induced estradiol deficiency by oophorectomy (OVX), hypertension, or both, and hemodynamic stress in 7-week-old female Sprague-Dawley rats. They were then given hormone-replacement therapy with 17beta-estradiol or an angiotensin II type 1 receptor blocker (ARB). The effects of estradiol, angiotensin II type 1 receptor blocker, or both on cultured endothelial cells were also examined.


RESULTS
The number of anomalously shaped endothelial cells was higher in OVX than hypertensive rats (P < 0.05). Rats subjected to hypertension and OVX exhibited a marked increase in the incidence of saccular cerebral aneurysms. Estradiol or angiotensin II type 1 receptor blocker treatment reduced this incidence (P < 0.05). The endothelial nitric oxide synthase (eNOS) mRNA level in the intracranial artery of OVX and hypertensive and OVX rats was low (P < 0.05). Immunohistochemically, the expression of eNOS and estrogen receptor alpha (ERalpha) in the vascular wall of hypertensive and OVX rats was decreased; angiotensin II and the nicotinamide adenine dinucleotide phosphate oxidase subunits nicotinamide adenine dinucleotide phosphate oxidase 4 and p22phox were strongly expressed in cerebral aneurysms. In the absence of estradiol, eNOS was downregulated and nicotinamide adenine dinucleotide phosphate oxidase expression was increased in endothelial cells; angiotensin II augmented these phenomena. The regulation of eNOS was mediated by ERalpha. These results suggest that estrogen deficiency induces endothelial dysfunction and reactive oxygen species generation, triggering endothelial damage that leads to cerebral aneurysms and that hypertension is an additional risk factor.


CONCLUSIONS
A therapy targeted at the endothelium and management of hypertension may help to prevent cerebral aneurysms.
Tamura
Tetsuya
T
Department of Neurosurgery, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan. ttamura0415@yahoo.co.jp
Jamous
Mohammad A
MA
Kitazato
Keiko T
KT
Yagi
Kenji
K
Tada
Yoshiteru
Y
Uno
Masaaki
M
Nagahiro
Shinji
S
D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure; D016319:Corrosion Casting; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D004958:Estradiol / Q000097:blood / Q000172:deficiency / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications; D002532:Intracranial Aneurysm / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017931:DNA Primers; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D009569:Nitric Oxide; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C077793:candesartan cilexetil