title: Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging.
abstract: 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 ([Ca(2+)](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 [Ca(2+)](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)F(2alpha) and prostacyclin (PGI(2)) increased by ACh; only PGF(2alpha) caused contraction at relevant concentrations. COX-2 expression, ACh-stimulated contractions, and vascular sensitivity to PGF(2alpha) were augmented in aortae from aged hamsters. Human renal arteries also showed thromboxane-prostanoid receptor-mediated ACh- or PGF(2alpha)-induced contractions and COX-2-dependent release of PGF(2alpha). The present study demonstrates that PGF(2alpha), 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 [Ca(2+)](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.
authors.affiliation: Institute of Vascular Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.forename: Fung Ping
authors.initials: FP
authors.lastname: Leung
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.forename: Chak Leung
authors.initials: CL
authors.lastname: Au
authors.forename: Lai Ming
authors.initials: LM
authors.lastname: Yung
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015237:Dinoprost / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism; D012077:Renal Artery / Q000201:enzymology; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D015237:Dinoprost; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000109:Acetylcholine; D002118:Calcium