HENRY M JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY M
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.