17beta-estradiol decreases vascular tone in cerebral arteries by shifting COX-dependent vasoconstriction to vasodilation.
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.
Ospina
Jose A
JA
Department of Pharmacology, College of Medicine, University of California, Irvine, CA 92697-4625, USA.
Duckles
Sue P
SP
Krause
Diana N
DN
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002536:Cerebral Arteries / Q000187:drug effects*; D051545:Cyclooxygenase 1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins; D009119:Muscle Contraction / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D011312:Pressure; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D014599:Uterus / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D007527:Isoenzymes; D008565:Membrane Proteins; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D004958:Estradiol; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003577:Cytochrome P-450 Enzyme System; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase