Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging.
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.
Wong
Siu Ling
SL
Institute of Vascular Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Leung
Fung Ping
FP
Lau
Chi Wai
CW
Au
Chak Leung
CL
Yung
Lai Ming
LM
Yao
Xiaoqiang
X
Chen
Zhen-Yu
ZY
Vanhoutte
Paul M
PM
Gollasch
Maik
M
Huang
Yu
Y
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
D017382:Reactive Oxygen Species; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D015237:Dinoprost; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000109:Acetylcholine; D002118:Calcium