Estrogen Replacement Suppresses a Prostaglandin H Synthase–Dependent Vasoconstrictor in Rat Mesenteric Arteries

From the Perinatal Research Centre, Departments of Ob/Gyn and Physiology, University of Alberta, Edmonton, AB Canada T6G 2S2.

Correspondence to Sandra T. Davidge, PhD, 220 Heritage Medical Research Centre, University of Alberta, Edmonton, AB Canada T6G 2S2. E-mail sandra.davidge{at}ualberta.ca

Abstract—There is evidence that estrogen can upregulate nitric oxide (NO) synthase expression. There is also evidence that NO increases the activity of prostaglandin H synthase (PGHS). Our initial hypothesis was that removal of ovarian steroids would decrease endothelium/NO-dependent relaxation responses but that estrogen replacement would increase NO and PGHS activity, leading to increased vasodilation. Resistance-sized (<250 µm) mesenteric arteries from ovariectomized Sprague-Dawley rats without and with 17ß-estradiol replacement (0.15 or 0.5 mg/pellet, 60-day release) for 4 weeks were studied in a myograph system. The vasodilator response to methacholine, an endothelium-dependent muscarinic agonist, was reduced in the arteries of the ovariectomized rats compared with estradiol-replaced rats. In the presence of PGHS inhibitors (meclofenamate, valeryl salicylate, and NS-398) or a thromboxane A₂ (TxA₂)/prostaglandin H₂ (PGH₂) receptor blocker (SQ-29548), there was no longer a significant difference among the groups. Contrary to our initial hypothesis, inhibition of the PGHS pathway significantly enhanced the relaxation response in the arteries from the ovariectomized rats, which was similar to the response in the arteries from estradiol-replaced rats, indicating that a PGHS-dependent vasoconstrictor had modified the response to methacholine. Confirming these data, in response to exogenous arachidonic acid, arteries from ovariectomized rats exhibited constriction, whereas the arteries from the estradiol-replaced rats exhibited vasodilation. In the ovariectomized rats, pretreatment with inhibitors of the PGHS pathway reversed the vasoconstriction to a vasodilation. In addition, the vasoconstrictor response to the thromboxane mimetic U-46619 as well as PGH₂ was enhanced in endothelium-denuded arteries from the ovariectomized rats compared with the estradiol-replaced rats. These data demonstrate that removal of ovarian steroids increased endothelium-mediated PGHS-dependent vasoconstriction that was associated with augmented sensitivity of the TxA₂/PGH₂ receptor. Chronic estrogen replacement in the ovariectomized rat suppressed this PGHS-dependent vasoconstrictor response.

Key Words: estrogen, vascular • endothelium • nitric oxide • prostaglandin

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