17β-Estradiol Increases Rat Cerebrovascular Prostacyclin Synthesis by Elevating Cyclooxygenase-1 and Prostacyclin Synthase

Abstract

Background and Purpose-It has been reported that estrogens modulate peripheral vascular synthesis of vasodilatory hormones, including prostacyclin. If this occurs in the cerebral circulation, it could have important consequences in the modulation of cerebral hemodynamic function and improvement of stroke outcome. We investigated the hypothesis that in vivo 17␤-estradiol treatment of ovariectomized rats increases cerebrovascular prostacyclin production via elevation of the enzymes responsible for prostacyclin synthesis. Methods-Cerebral blood vessels from 17␤-estradiol-treated and nontreated ovariectomized rats were isolated and examined for prostacyclin synthesis by enzyme-linked immunosorbent assay or for protein levels of cyclooxygenase-1, prostacyclin-synthase, and cytosolic phospholipase A 2 by immunoblot analysis. Results-We report that chronic in vivo 17␤-estradiol treatment significantly enhanced basal prostacyclin synthesis in rat cerebral blood vessels by 2.6-fold over control. 17␤-Estradiol treatment also resulted in a 5.1-fold increase of cyclooxygenase-1 protein and a 6.7-fold increase of prostacyclin-synthase protein in the cerebral vasculature. There was no effect of estrogen on levels of cytosolic phospholipase A 2 . Conclusions-Our findings suggest that estrogen influences the biosynthesis of prostacyclin, which may be important in the regulation of cerebral blood flow and thrombosis. This finding may shed light on the mechanisms that govern sex-based differences in cerebrovascular disease. (Stroke. 2002;33:600-605.)

Effects of estrogen on the vascular system

“…Increased levels of PGI 2 upon stimulation with estradiol have been associated with increased expression of the key enzymes involved in PGI 2 production, phospholipase A 2 , COX-1, and prostacyclin synthetase (PGIS), as demonstrated in rat cerebral blood vessels, where chronic in vivo 17ß-estradiol treatment enhances basal PGI 2 synthesis by increasing COX-1 and PGIS proteins (27). It seems that the COX-2 pathway also plays a specific role in estradiol-induced PGI 2 synthesis and vasodilation.…”

Estradiol Regulation of Prostanoids Production in Endothelium

“…In the vast majority of experiments, cells were exposed to estradiol during 24-48 hours, and the increase of prostacyclin above control values ranged from 16 % to 78 % (Table 1). In addition, it has been shown that estradiol stimulates production of prostaglandins in a variety of preparations of arteries, including ovine uterine arteries (Vagnoni & Magness, 1998;Janowiak et al, 1998;Habermehl et al, 2000), mesenteric arteries from ovariectomized rats (Davidge & Zhang, 1998;Armstrong et al, 2002), rat cerebral blood vessels (Ospina et al, 2002;Ospina et al, 2003), and aorta from ovariectomized monkeys (O'Sullivan et al, 2001). The increase of prostacyclin production is of a similar magnitude to that obtained with cultured endothelial cells.…”

“…Prostacyclin increased levels after vessel stimulation with estradiol have been mainly associated with enhanced expression of COX-1. In this way, COX-1 protein content is increased in rat (Ospina et al, 2002) and mice (Geary et al, 2001) cerebral blood vessels, and in ovine uterine arteries in response to treatment with estrogen (Rupnow et al, 2002). Indeed, COX-1 (but not COX-2) expression is increased in the endothelium of the ovine uterine artery during the follicular phase of the ovarian cycle and during pregnancy, where estrogen levels are highest (Janowiak et al, 1998;Habermehl et al, 2000).…”

Regulated expression of the prostacyclin receptor (IP) gene by androgens within the vasculature: Combined role for androgens and serum cholesterol

“…As stated, the cardioprotective effects of prostacyclin and of the female hormone estrogen (E2) are well documented [21]. Indeed expression of the prostacyclin receptor (IP) gene, the PTGIR, can be directly regulated by E2 which occurs through a transcriptional mechanism involving direct binding of the estrogen receptor (ER)α to a conserved estrogen response element (ERE) within the promoter region of the PTGIR [23].…”