Effect of oral HRT on ischemic cerebral vessels of young and aged rats

最近的数据表明，激素替代疗法（HRT）可能会加重中风的风险，但潜在的 一旦发生脑缺血事件，HRT对脑抢救的益处研究很少。新兴 有假说认为绝经后开始HRT时机可能很重要。本研究 侧重于缺血后再灌注期间HRT潜在有益作用的机制。 我们已经证明，在年轻的卵巢切除者中，软膜血管对血管扩张剂的反应明显降低， 雌激素恢复缺血后的舒张能力。在这些研究中，我们扩展了我们以前的工作， 以确定口服HRT是否通过减少血管舒张产物来改变脑血管反应， 花生四烯酸（AA）代谢，如果这些影响存在于年轻和老年雌激素缺乏 雌性大鼠因为HRT处方妇女往往包括口服雌激素（17 β-雌二醇，E），结合 马雌激素（CE）和天然孕酮（P），或甲羟孕酮（MP），我们使用临床相关的 剂量的E、CE、P和MP，并口服给药。我们的目标是确定口服HRT：1）改变 基底和缺血后软膜血管对血管扩张剂的反应性，如果这些效应在年轻人和 和老年雌激素缺乏大鼠，2）改变缺血后脑血管环氧合酶-2的表达 （考克斯-2）和前列腺素E2、前列环素和血栓素的产生，3）改善缺血后软脑膜炎， 通过考克斯-2介导的机制改变直径的动脉能力，如果这种作用存在于老年人， 雌激素缺乏的大鼠，并确定4）如果降低缺血后软膜动脉血管舒张能力， 如果E通过20-HETE合成调节缺血后软脑膜动脉血管舒张能力， 涉及细胞色素P450/AA代谢物的机制。所有研究均使用4血管闭塞模型， 脑缺血;在一些研究中，闭合的颅窗用于评价软脑膜动脉的变化 应答为了评估脑血管雌激素受体和AA产物合成的变化，我们 分离脑微血管并使用酶联免疫测定和Western印迹技术。这 该项目将通过以下方式提供新的信息：1）区分HRT中E与P的影响，2）比较 年轻和老年，雌激素缺乏大鼠之间的反应，3）不仅关注AA代谢物， 考克斯-2，但也对细胞色素P450，这还没有得到很好的研究，在脑再灌注。

Recent data suggest that hormone replacement therapy (HRT)can worsen risk for stroke, but the potential benefits of HRT on brain rescue once a cerebral ischemic event occurs have been poorly studied. Emerging hypotheses suggest that timing at which HRT is initiated after menopause might be important. This study focuses on mechanisms underlying the potential beneficial effects of HRT during postischemic reperfusion. We have shown that pial vascular reponses to vasodilators are markedly depressed in young ovariectomized rats and that estrogen restores postischemic dilatory capacity. In these studies, we extend our previous work to determine if oral HRT alters cerebrovascular responses by decreasing vasodilatory products of arachidonic acid (AA)metabolism and if these effects are present in young and aged estrogen-deficient female rats. Because HRT prescribed for women often includes oral estrogen (17p-estradiol, E), conjugated equine estrogen (CE)and natural progesterone (P),or medroxyprogesterone (MP), we use clinically relevant dosages of E, CE, P, and MP, and administer the drugs orally. We aim to determine if oral HRT:1) alters basal and postischemic pial vessel reactivity to vasodilators and if these effects are present in both young and aged, estrogen-deficient rats, 2) alters postischemic cerebral vessel expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2, prostacyclin, and thromboxane, 3) improves postischemic pial artery capacity to change diameter via COX-2-mediated mechanisms and if this effect is present in aged, estrogen-deficient rats, and to ascertain 4) if depressed postischemic pial artery vasodilator capacity is modulated by 20-HETE synthesis and if E improves postischemic pial artery vasodilatory capacity via mechanisms involving cytochrome P450/AA metabolites. All studies use a 4-vessel occlusion model of cerebral ischemia; in some studies, a closed cranial window is used to evaluate changes in pial artery responses. To evaluate changes in cerebrovascular estrogen receptors and synthesis of AA products, we isolate cerebral microvessels and use enzyme-linked immunoassay and Western Blot techniques. This project will provide novel information by 1) distinguishing the effects of E from P in HRT, 2) comparing responses between young and aged, estrogen-deficient rats, 3) focusing not only on AA metabolites of COX-2, but also on cytochrome P450, which have not been well studied during cerebral reperfusion.