17β-Estradiol decreases vascular tone in cerebral arteries by shifting COX-dependent vasoconstriction to vasodilation

Abstract

We have previously shown that estrogen treatment increases cerebrovascular cyclooxygenase-1, prostacyclin synthase, and production of prostacyclin. Therefore, vascular tone and prostanoid production were measured to investigate functional consequences of estrogen exposure. Middle cerebral arteries were isolated from ovariectomized female Fischer-344 rats with or without chronic in vivo 17beta-estradiol treatment. In vivo 17beta-estradiol treatment increased cerebral artery diameter; functional endothelium was required for expression of these differences. The nonspecific cyclooxygenase inhibitor indomethacin constricted, whereas arachidonic acid dilated, cerebral arteries from estrogen-treated animals. Estrogen exposure increased production of prostacyclin by cerebral arteries. Conversely, in estrogen-deficient animals, indomethacin dilated and arachidonic acid constricted cerebral blood vessels. This correlated with vasorelaxation following inhibition of the thromboxane-endoperoxide receptor with SQ-29548 but not after selective blockade of thromboxane synthase with furegrelate, suggesting prostaglandin endoperoxide (i.e., PGH2) activity. Removal of the endothelium or selective blockade of cyclooxygenase-1 with SC-560 abolished estrogen-mediated differences in the effects of arachidonate on vessel diameter and on prostacyclin production by cerebral arteries. These data suggest 17beta-estradiol decreases cerebrovascular tone by shifting the primary end product of the endothelial cyclooxygenase-1 pathway from the constrictor prostaglandin PGH2 to the vasodilator prostacyclin. These effects of estrogen may contribute to the heightened thromboresistance and enhanced cerebral blood flow documented in pre-versus postmenopausal women.

Characteristics of contractile activity in the renal artery of ovariectomized rats

“…Studies have shown that estrogen may regulate vascular tone in the cerebral artery by shifting cyclooxygenase-1 (COX-1)-dependent vasodilatation or vasoconstriction (Ospina et al, 2003;Jun et al, 1998). Indomethacine significantly, albeit slightly, affected contractile responses to PE in the current investigation; however, no differences were detected among the three groups (data not shown).…”

“…The 17β-estradiol treatment, which was initiated one month post-ovariectomy, was continued at 17 µg for 2 weeks, which may, in part, account for our findings. Several investigations described implementation of 17β-estradiol treatment concomitant with ovariectomy; furthermore, this regime led to normalization of body and uterine weights of ovariectomized rats (Davidge et al, 1998;Ospina et al, 2003;Teede et al, 2001). Alteration of fatty acid composition in the uterus of OVX rats was significantly different from that in control rats and the changes were slightly reduced by treatment with 17β-estradiol (Table 2).…”

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

“…Several reports indicate that ischemia rapidly stimulates marked expression of the inflammatory mediator IL-1b in brain (Minami et al, 1992;Buttini et al, 1994) and in cerebral vessels (Zhang et al, 1998). Recent data confirm a relationship between IL-1b, amplification of PGE 2 synthesis, and reduction of cerebral vascular tone (Ospina et al, 2003;Ospina et al, 2004). Other studies indicate that cerebral ischemia and reperfusion increases expression of COX-2 with subsequent increased synthesis of the vasodilator PGE 2 (Catley et al, 2003).…”

Estrogens and Brain

“…Эстроген сдвигает баланс синтеза про-станоидов к вазодилататору -простациклину (PGI 2 ). Е 2 увеличивает продукцию PGI 2 через стимуляцию циклооксигеназы 1 (ЦОГ1) и PGI 2 -синтазы в цере-бральных сосудах [39]. При этом эффекты эстрогена на ЦОГ1 более выражены в отсутствие активности нитроксидсинтазы.…”

“…Противовоспалительное действие Е 2 проявляется в подавлении индукции ЦОГ2 в церебральных сосудах под действием ИЛ-1β и блокаде миграции клеток микро-глии в очаг воспаления [39]. Эстрадиол предотвращает не только активацию микроглии, но и мобилизацию пери-ферических мононуклеаров в структуры мозга при вну-трижелудочковой инъекции липополисахарида.…”