Wassmann S, Bäumer A T, Strehlow K, van Eickels M, Grohé C, Ahlbory K, Rösen R, Böhm M, Nickenig G
Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Circulation. 2001 Jan 23;103(3):435-41. doi: 10.1161/01.cir.103.3.435.
Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT(1)) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT(1) receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17beta-estradiol.
Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT(1) receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription-polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT(1) receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals.
In SHR, estrogen deficiency leads to increased vascular free radical production and enhanced angiotensin II-induced vasoconstriction via increased vascular AT(1) receptor expression, resulting in endothelial dysfunction. Estrogen replacement therapy and AT(1) receptor antagonism prevent these pathological changes. Therefore, estrogen deficiency-induced AT(1) receptor overexpression and oxidative stress may play an important role in cardiovascular diseases associated with menopause.
绝经后雌激素缺乏与心血管风险增加、高血压及氧化应激相关。1型血管紧张素（AT(1)）受体调节参与动脉粥样硬化的发病机制。为了明确雌激素缺乏期间的血管功能、氧化应激及AT(1)受体调节情况，将去卵巢的自发性高血压大鼠（SHR）与假手术动物及接受17β-雌二醇雌激素替代疗法的去卵巢大鼠进行比较研究。
所研究的3组动物的动脉血压相似。去卵巢5周后，观察到主动脉环存在内皮功能障碍，雌激素替代疗法可使其逆转。雌激素缺乏导致血管紧张素II引起的血管收缩增强。通过光泽精化学发光测定法测得，与假手术大鼠相比，血管超氧化物生成显著增加。雌激素替代使血管壁自由基生成恢复正常。定量逆转录-聚合酶链反应显示，雌激素缺乏显著上调血管AT(1)受体表达，而内皮型一氧化氮合酶mRNA表达及NO释放未改变。用AT(1)受体拮抗剂厄贝沙坦对动物进行5周治疗可预防去卵巢大鼠的内皮功能障碍，并使血管自由基生成恢复正常。
在SHR中，雌激素缺乏通过增加血管AT(1)受体表达导致血管自由基生成增加及血管紧张素II诱导的血管收缩增强，从而引起内皮功能障碍。雌激素替代疗法及AT(1)受体拮抗作用可预防这些病理变化。因此，雌激素缺乏诱导的AT(1)受体过表达及氧化应激可能在绝经相关心血管疾病中起重要作用。
