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Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats.
J Hypertens. 2009 Jun; 27(6):1284-92.JH

Abstract

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.

CONCLUSION

A therapy targeted at the endothelium and management of hypertension may help to prevent cerebral aneurysms.

Authors+Show Affiliations

Department of Neurosurgery, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan. ttamura0415@yahoo.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19307983

Citation

Tamura, Tetsuya, et al. "Endothelial Damage Due to Impaired Nitric Oxide Bioavailability Triggers Cerebral Aneurysm Formation in Female Rats." Journal of Hypertension, vol. 27, no. 6, 2009, pp. 1284-92.
Tamura T, Jamous MA, Kitazato KT, et al. Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J Hypertens. 2009;27(6):1284-92.
Tamura, T., Jamous, M. A., Kitazato, K. T., Yagi, K., Tada, Y., Uno, M., & Nagahiro, S. (2009). Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. Journal of Hypertension, 27(6), 1284-92. https://doi.org/10.1097/HJH.0b013e328329d1a7
Tamura T, et al. Endothelial Damage Due to Impaired Nitric Oxide Bioavailability Triggers Cerebral Aneurysm Formation in Female Rats. J Hypertens. 2009;27(6):1284-92. PubMed PMID: 19307983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. AU - Tamura,Tetsuya, AU - Jamous,Mohammad A, AU - Kitazato,Keiko T, AU - Yagi,Kenji, AU - Tada,Yoshiteru, AU - Uno,Masaaki, AU - Nagahiro,Shinji, PY - 2009/3/25/entrez PY - 2009/3/25/pubmed PY - 2009/8/26/medline SP - 1284 EP - 92 JF - Journal of hypertension JO - J Hypertens VL - 27 IS - 6 N2 - 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. CONCLUSION: A therapy targeted at the endothelium and management of hypertension may help to prevent cerebral aneurysms. SN - 1473-5598 UR - https://www.unboundmedicine.com/medline/citation/19307983/Endothelial_damage_due_to_impaired_nitric_oxide_bioavailability_triggers_cerebral_aneurysm_formation_in_female_rats_ L2 - https://doi.org/10.1097/HJH.0b013e328329d1a7 DB - PRIME DP - Unbound Medicine ER -