Tamura Tetsuya, Jamous Mohammad A, Kitazato Keiko T, Yagi Kenji, Tada Yoshiteru, Uno Masaaki, Nagahiro Shinji
Department of Neurosurgery, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan.
J Hypertens. 2009 Jun;27(6):1284-92. doi: 10.1097/HJH.0b013e328329d1a7.
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.
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.
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.
A therapy targeted at the endothelium and management of hypertension may help to prevent cerebral aneurysms.
流行病学数据表明绝经后女性脑动脉瘤发病率较高。为阐明脑动脉瘤的发病机制，我们重点研究了大鼠内皮损伤的作用。
我们通过卵巢切除术（OVX）、高血压或两者兼而有之，在7周龄雌性Sprague-Dawley大鼠中诱导雌二醇缺乏和血流动力学应激。然后给它们用17β-雌二醇或1型血管紧张素II受体阻滞剂（ARB）进行激素替代治疗。还检测了雌二醇、1型血管紧张素II受体阻滞剂或两者对培养内皮细胞的影响。
OVX大鼠中异常形状的内皮细胞数量高于高血压大鼠（P < 0.05）。患有高血压和OVX的大鼠囊状脑动脉瘤的发病率显著增加。雌二醇或1型血管紧张素II受体阻滞剂治疗可降低该发病率（P < 0.05）。OVX大鼠、高血压大鼠和高血压合并OVX大鼠颅内动脉中的内皮型一氧化氮合酶（eNOS）mRNA水平较低（P < 0.05）。免疫组织化学显示，高血压大鼠和OVX大鼠血管壁中eNOS和雌激素受体α（ERα）的表达降低；血管紧张素II以及烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基烟酰胺腺嘌呤二核苷酸磷酸氧化酶4和p22phox在脑动脉瘤中强烈表达。在缺乏雌二醇的情况下，内皮细胞中eNOS下调，烟酰胺腺嘌呤二核苷酸磷酸氧化酶表达增加；血管紧张素II加剧了这些现象。eNOS的调节由ERα介导。这些结果表明，雌激素缺乏会诱导内皮功能障碍和活性氧生成，引发导致脑动脉瘤的内皮损伤，而高血压是一个额外的危险因素。
针对内皮的治疗和高血压管理可能有助于预防脑动脉瘤。
