doi: 10.1161/CIRCRESAHA.108.192526
© 2009 American Heart Association, Inc.
Editorials |
Cyclooxygenase-2-Derived Prostaglandin F2
An Endothelium-Derived Contractile Factor Acting Independently of Other Endothelium-Derived Contractile Factors via Vascular Thromboxane Receptors
From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Germany.
Correspondence to Karsten Schrör, Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Moorenstr. 5, D-40225 Düsseldorf, Germany. E-mail karsten.schroer{at}uni-duesseldorf.de
See related article, pages 228–235
Key Words: EDCF • hamster aorta • PGF2
• thromboxane receptors
Soluble vasoactive factors derived from vascular endothelium modulate the tone of underlying smooth muscle cells. Stimulation of intact, ie, endothelialized, vessels with acetylcholine causes vasodilation by release of endothelium-derived relaxing factors (EDRFs), mostly NO and hyperpolarizing factor(s) (EDHF). The endothelium also produces contractile factors (EDCF) of different origin.1 Thus, any reduced endothelium-dependent relaxation or even vasoconstriction could result from either loss of EDRFs, (enhanced) generation of EDCFs, or a combination of both. EDCF-mediated vasoconstriction might prevail with increasing age, as well as disturbed endothelial function, for example, in hypertension1,2 or type 2 diabetes.3 In addition to reduced generation of vasodilator prostaglandins (PGs), such as PGI2, enhanced production of vasoconstrictor prostanoids has been described.4,5 Oxygen-derived free radicals and isoprostanes, generated by exaggerated oxidative stress, are further members of the EDCF family. Thus, EDCFs represent an inhomogeneous group of compounds with different chemical identity.
In the few last years, vasocontractile prostanoids, generated by endothelial cyclooxygenase(s) (COX[s]), have come into focus as significant EDCFs.1 One reason for this is the upregulation of endothelial COXs and enzymes of PG-endoperoxide catabolism during the aging process and hypertension with enhanced generation of these compounds6,7; another reason is the low selectivity of prostanoids for their membrane receptors. Vasoconstrictor prostanoids act on vascular smooth muscle cells via the thromboxane-prostanoid (TP) receptor.8 However, reactive oxygen species and other primary PGs, including PGI2 at higher concentrations,9 may also activate this receptor and cause vasoconstriction.
In this issue of Circulation Research, Wong and colleagues10 demonstrate generation of a prostanoid-type EDCF in the hamster aorta in vitro. Treatment of the vessels with nonselective inhibitors of COX-1/2 or selective COX-2 inhibitors prevented these contractions, whereas selective COX-1 inhibitors were ineffective. This suggests a constitutively expressed COX-2 as source of EDCF formation. Although earlier studies had already considered COX-2-derived prostanoids as EDCFs,3,6,11 the present study identifies a less well-known product, PGF2, as the only EDCF in this particular model. The acetylcholine-induced generation of PGF2 (and PGI2) in intact hamster aortae disappeared after endothelial denudation. Any vasomotor action of other prostanoids and PGI2 could be excluded, as well as the involvement of the prostacyclin receptor for signal transduction.
Endothelial COXs, rather than those of vascular smooth muscle cells, are the main source of PG-endoperoxide generation in the vessel wall,12 the immediate precursors of terminal PGs. In SHR rats, enhanced COX-1 expression was found to be associated with generation of EDCFs,13 possibly PG endoperoxides and PGI21. However, in other species including humans, PGI2 is generated by both endothelial COX-1 and COX-2,14 and it is the COX-2, rather than COX-1 (ie, the regulated form of the enzyme) that synthesizes the majority of vascular PGs. Thus, the demonstration of an entirely COX-2-dependent EDCF formation could have some impact.
All prostanoids signal via G protein-coupled membrane receptors. Stimulation of TP receptors increases Ca2+ entry by opening of both voltage- and receptor-operated channels, with subsequent increase in cytosolic Ca2+ and smooth muscle contraction. TP receptors are not selective for thromboxane but may also bind other prostanoids.15 In the study of Wong et al,10 acetylcholine-induced aortic contractions were attenuated or abolished by 3 structurally different thromboxane receptor antagonists but not by an antagonist to the F-series-prostanoid (FP) receptor, ie, the specific binding site for PGF2. Other potential candidates for TP-mediated contractions of smooth muscle cells, such as 8-isoprostanes, PGI2, PGE2, and oxygen-derived free radicals,8,9,16,17 could be excluded. Thus, the EDCF, stimulated by acetylcholine and acting via the TP receptor, was most likely PGF2.
Endothelium-dependent contractions are augmented with aging, involve both COX-1 and COX-2, and are potentiated by oxidative stress.6 In the study of Wong et al,10 there were larger contractions in aortae from aged as compared to young hamsters. This was explained by an age-related reduced generation of EDRF. The expression of TP receptors remained unchanged, similar to another study from the same group in aged rats.7 In this study on normotensive and hypertensive rats, genomic expression of endothelial COX-1 was increased, suggesting a greater potency to generate and release EDCFs in aging and hypertension.7 A significant contribution of COX-1-derived EDCFs in the study of Wong et al10 in hamsters is unlikely. Thus, there might be species differences not only regarding the chemical identity of EDCF(s) but also the biosynthetic pathways and site(s) of action. Hirao et al11 have shown that the EDCF, generated by reendothelialized femoral artery of rats 4 weeks after photochemical endothelial injury, was mainly PGF2 and PGH2 but not thromboxane A2. This would confirm PGF2 as EDCF, contributing to the reduced vasodilation of reendothelialized femoral arteries.
What is the significance of these data for humans? First, it should be noted that COX-2 was the main enzyme involved in EDCF, ie, PGF2 release in the hamster aorta. In humans, COX-2 rather than COX-1 produces the majority of vascular PGs in healthy14 and atherosclerotic areas.18 However, PGF2 is certainly not a major product, but rather PGI2 and PGE2 are both potent vasodilators in most vascular beds of humans. In contrast to this, COX-1 is the main regulated enzyme in the rat aorta,19 in which many studies on the identity of EDCF were performed.1 Thus, the prostanoid synthetic pathways in humans appear to be closer to the hamster than the rat, as also suggested by the authors.
Regarding TP receptors, the authors present some preliminary data suggesting an EDCF/PGF2-mediated contraction of renal arteries in hypertensive diabetics. These contractions were mimicked by exogenous PGF2 and antagonized by antagonists of TP but not FP receptors. Thus, PGF2 might also act as EDCF via the TP receptor in humans. Further studies have to establish this. The VIGOR study demonstrated an increase rather than decrease of blood pressure with the selective COX-2 inhibitor rofecoxib in patients with elevated cardiovascular risk.20 This raises the question for a (patho)physiological role of COX-2-derived PGF2 acting as EDCF via TP receptors in humans. Because of its relatively low endothelial production rate as opposed to PGI2 and/or PGE2, both being vasodilators, and the short half-life of circulating PGF2 (<1 minute), this appears to be less likely. In a recent review by the same group, the contribution of PGF2 to endothelium-dependent contraction has been considered marginal.1 On the other hand, there might be situations, such as senescence, in which metabolic enzymes may become insufficient to degrade efficiently released PGs in conditions of elevated biosynthesis, including PGH2, thromboxane A2, and PGF2.21 Because of the rapid hydrolysis of thromboxane A2 into the inactive thromboxane B2 and the (spontaneous) conversion of PGH2 into PGF2, PGF2 may locally accumulate and cause vasoconstriction. For example, high levels of PGF2 were found in the cerebrospinal fluid of patients with cerebral transient ischemic attacks or stroke, even in the absence of subarachnoid hemorrhage.22
Overall, Wong et al10 have demonstrated convincing evidence for COX-2-derived PGF2 as an EDCF acting via TP receptor in the hamster aorta. This provides pharmacological evidence for TP receptor antagonists as useful tools to correct imbalances between EDRF/EDCF. This could be an argument for the revival of the concept of thromboxane receptor blockade to prevent regional ischemia. This concept must not necessarily be realized by thromboxane receptor antagonists, the development of which, unfortunately, has been stopped after the first larger clinical trials with these compounds failed. Natural vasodilator epoxyeicosatrienoic acids offer an alternative and were recently reported to cause vasodilation via competitive, direct inhibition of TP receptors.23
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Acknowledgments |
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Sources of Funding
None.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
|---|
1. Vanhoutte PM, Tang EHC. Endothelium-dependent contractions: when a good guy turns bad. J Physiol. 2008; 586: 5295–5304.
2. Taddei S, Virdis S, Mattei P, Ghiadoni L, Fasolo CB, Sudano I, Sakvetti A. Hypertension causes premature aging of endothelial function in humans. Hypertension. 1997; 29: 736–743.
3. Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Imbalance between endothelium-derived relaxing and contractile factors in mesenteric arteries from aged OLETF rats, a model of type 2 diabetes. Am J Physiol Heart Circ Physiol. 2007; 293: H1480–H1490.
4. Tokunaga O, Yamada T, Fan J, Watanabe T. Age-related decline in prostacyclin biosynthesis by human aortic endothelial cells. Am J Pathol. 1991; 138: 141–149.[Abstract]
5. Lennon EA, Poyser NL. Effect of age on vascular prostaglandin production in male and female rats. Prostagl Leukotr Med. 1986; 25: 1–15.[CrossRef]
6. Shi Y, Man RYK, Vanhoutte PM. Two isoforms of cyclooxygenase contribute to augmented endothelium-dependent contractions in femoral arteries of 1-year-old rats. Acta Pharmacol Sin. 2008; 29: 185–192.[CrossRef][Medline] [Order article via Infotrieve]
7. Tang EHC, Vanhoutte PM. Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiol Genomics. 2008; 32: 409–418.
8. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Thromboxane A2 receptor antagonists inhibit endothelium-dependent contractions. Hypertension. 1990; 15: 699–703.
9. Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, Feletou M. Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin. Br J Pharmacol. 2005; 146: 834–845.[CrossRef][Medline] [Order article via Infotrieve]
10. Wong SL, Leung FP, Lau CW, Au CL, Yung LM, Yao X, Chen Z-Y, Vanhoutte PM, Gollasch M, Huang Y. Cyclooxygenase-2-derived prostaglandin F2 mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging. Circ Res. 2009; 104: 228–235.
11. Hirao A, Kondo K, Takeuchi K, Inui N, Umemura K, Ohashi K, Watanabe H. Cyclooxygenase-dependent vaoconstricting factor(s) in remodelled rat femoral arteries. Cardiovasc Res. 2008; 79: 161–168.
12. DeWitt DL, Day JS, Sonnenburg WK, Smith WL. Concentrations of prostaglandin endoperoxide synthase and prostaglandin I2 synthase in the endothelium and smooth muscle of bovine aorta. J Clin Invest. 1983; 72: 1882–1888.[Medline] [Order article via Infotrieve]
13. Ge T, Hughes H, Junquero DC, Wu KK, Vanhoutte PM, Boulanger CM. Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res. 1995; 76: 1003–1010.
14. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2 – the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999; 96: 272–277.
15. Halushka PV, Allan CJ, Davis-Bruno KL. Thromboxane A2 receptors. J Lipid Med Cell Signal. 1995; 12: 361–378.[CrossRef][Medline] [Order article via Infotrieve]
16. Sametz W, Hennerbichler S, Glaser S, Wintersteiger R, Juan H. Characterization of prostanoid receptors mediating action of the isoprostanes, 8-iso-PGE2 and 8-iso-PGF2, in some isolated smooth muscle preparations. Br J Pharmacol. 2000; 130: 1903–1910.[CrossRef][Medline]
[Order article via Infotrieve]
17. Armstrong RA, Wilson NH. Aspects of the thromboxane receptor system. Gen Pharmac. 1995; 26: 463–472.[Medline] [Order article via Infotrieve]
18. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation. 2000; 102: 840–845.
19. Tang EHC, Jensen BL, Skott O, Leung GPH, Feletou M, Man RYK, Vanhoutte PM. The role of prostaglandin E and thromboxane-prostanoid receptors in the response to prostaglandin E2 in the aorta of Wistar Kyoto rats and spontaneously hypertensive rats. Cardiovasc Res. 2008; 78: 130–138.
20. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343: 1520–1528.
21. Lüscher TF, Boulanger CM, Yang Z, Noll G, Dohi Y. Interactions between endothelium-derived relaxing and contracting factors in health and cardiovascular disease. Circulation. 1993; 87 (suppl V): V-36–V-44.
22. Egg D, Herold M, Rumpl E, Günther R. Prostaglandin F2 levels in human cerebrospinal fluid in normal and pathological conditions. J Neurol. 1980; 222: 239–248.[CrossRef][Medline]
[Order article via Infotrieve]
23. Behm DJ, Ogbonna A, Wu C, Burns-Kurtis CL, Douglas SA. Epoxyeicoatrieneoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation. J Pharmacol Exp Ther. 2009; 328: 231–239.
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Mediates Endothelium-Dependent Contractions in the Aortae of Hamsters With Increased Impact During Aging
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