Published online before print December 18, 2008, doi: 10.1161/CIRCRESAHA.108.179770
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Submitted on May 20, 2008
Revised on December 2, 2008
Accepted on December 4, 2008
Cyclooxygenase-2–Derived Prostaglandin F2
Mediates Endothelium-Dependent Contractions in the Aortae of Hamsters With Increased Impact During Aging
Siu Ling Wong ;
From the Institute of Vascular Medicine (S.L.W., F.P.L., X.Y., Z.-Y.C., Y.H.) and Departments of Physiology (S.L.W., F.P.L., C.W.L., C.L.A., L.M.Y., X.Y., Y.H.) and Biochemistry (Z.-Y.C.), Chinese University of Hong Kong, China; Department of Pharmacology (P.M.V.), University of Hong Kong, China; and Medical Clinic for Nephrology and Internal Intensive Care (M.G.), Charité University Medicine Berlin, Germany.
* To whom correspondence should be addressed. E-mail: yu-huang{at}cuhk.edu.hk.
Hypertension and vascular dysfunction result in the increased release of endothelium-derived contracting factors (EDCFs), whose identity is poorly defined. We tested the hypothesis that endothelial cyclooxygenase (COX)-2 can generate EDCFs and identified the possible EDCF candidate. Changes in isometric tension of aortae of young and aged hamsters were recorded on myograph. Real-time changes in intracellular calcium concentrations ([Ca2+]i) in native aortic endothelial cells were measured by imaging. Endothelium-dependent contractions were triggered by acetylcholine (ACh) after inhibition of nitric oxide production and they were abolished by COX-2 but not COX-1 inhibitors or by thromboxane–prostanoid receptor antagonists. 2-Aminoethoxydiphenyl borate (cation channel blocker) eliminated endothelium-dependent contractions and ACh-stimulated rises in endothelial cell [Ca2+]i. RT-PCR and Western blotting showed COX-2 expression mainly in the endothelium. Enzyme immunoassay and high-performance liquid chromatography/coupled mass spectrometry showed release of prostaglandin (PG)F2
and prostacyclin (PGI2) increased by ACh; only PGF2 caused contraction at relevant concentrations. COX-2 expression, ACh-stimulated contractions, and vascular sensitivity to PGF2 were augmented in aortae from aged hamsters. Human renal arteries also showed thromboxane–prostanoid receptor–mediated ACh- or PGF2-induced contractions and COX-2–dependent release of PGF2. The present study demonstrates that PGF2, derived from COX-2, which is localized primarily in the endothelium, is the most likely EDCF underlying endothelium-dependent, thromboxane–prostanoid receptor–mediated contractions to ACh in hamster aortae. These contractions involved increases in endothelial cell [Ca2+]i. The results support a critical role of COX-2 in endothelium-dependent contractions in this species with an increased importance during aging and, possibly, a similar relevance in humans.
Key words: endothelium-derived contracting factors • cyclooxygenase-2 • thromboxane–prostanoid receptor • aging • aorta
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