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)可以恶化中风的风险，但潜在的 一旦发生脑缺血事件，HRT在脑抢救中的益处一直没有得到充分的研究。新兴 假说表明，绝经后开始激素替代疗法的时间可能很重要。本研究 重点阐述了HRT在缺血后再灌流过程中潜在有益作用的机制。 我们已经证明，年轻的卵巢切除患者对血管扩张剂的软脑膜血管反应明显受到抑制。 而雌激素可以恢复缺血后的扩张能力。在这些研究中，我们扩展了我们以前的工作 确定口服HRT是否通过减少血管扩张产物而改变脑血管反应 花生四烯酸(AA)代谢以及这些影响是否存在于年轻和老年雌激素缺乏患者 雌性老鼠。因为为女性开的HRT通常包括口服雌激素(17P-雌二醇，E)，结合 马雌激素(CE)和自然孕酮(P)，或甲羟孕酮(MP)，我们使用临床相关 E、CE、P、MP剂量，口服给药。我们的目标是确定口服HRT：1)是否会改变 基础和缺血后软脑膜血管对血管扩张剂的反应性以及这些效应是否存在于 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 (COX-2)和前列腺素E_2、前列环素和血栓素的产生，3)改善缺血后软脑膜 通过COX-2介导的机制改变动脉直径的能力，如果这种影响存在于老年人， 雌激素缺乏的大鼠，并确定4)是否抑制缺血后软脑膜动脉的血管扩张剂能力 受20-HETE合成的调节，IF E通过 涉及细胞色素P450/AA代谢产物的机制。所有研究均采用四支血管闭塞模型。 脑缺血；在一些研究中，关闭的颅窗被用来评估软脑膜动脉的变化 回应。为了评估脑血管雌激素受体的变化和AA产物的合成，我们 分离脑微血管，采用酶联免疫分析和Western Blot技术。这 该项目将提供新的信息，1)区分E和P在HRT中的影响，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 COX-2的表达，以及细胞色素P450的表达，在脑再灌注过程中还没有得到很好的研究。

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.