Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries.
The vasodilator effects of thrombin depend on activation of proteinase-activated receptor (PAR)-1 and the subsequent release of endothelin (ET)-1, which stimulates the generation of nitric oxide and PGs. We recently showed that thrombin released matrix metalloproteinase-2 (MMP-2) from rat arteries. We have now studied the significance of this release for the vasodilator effects of thrombin. Thrombin (>/=100 pmol), but not a PAR-1-activating peptide (TFLLR-NH(2)), produced a long-lasting (>10 min) vasorelaxation of rat mesenteric arteries, as detected by a microperfusion bioassay. Thrombin induced a simultaneous release of vascular MMP-2 into arterial perfusates, as revealed by zymography. Interestingly, the vasodilator effects of thrombin were inhibited by a tissue inhibitor of MMP-2 (TIMP-2, 10 pmol). Moreover, infusion of exogenous MMP-2 (5 pmol) resulted in vasorelaxation. These vasodilatory effects of thrombin and MMP-2 were significantly (P < 0.05) inhibited by endothelium denudation and by PD-142893 (2 nmol), an antagonist of ET receptors. Furthermore, both thrombin and MMP-2 constricted endothelium-denuded arteries. These results show that the vasodilator effects of thrombin may depend, in part, on a release of vascular MMP-2 and downstream activation of ETs. Thus MMP-2-dependent signaling may complement the PAR-1-dependent pathway of vasodilator action of thrombin.
Fernandez-Patron
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Perinatal Research Centre, Departments of Obstetrics/Gynaecology and Physiology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Radomski
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MW
Davidge
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006490:Hemostatics / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008638:Mesenteric Arteries / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D044463:Receptor, PAR-1; D017466:Receptors, Endothelin / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D006490:Hemostatics; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D044023:Receptor, Endothelin B; D044463:Receptor, PAR-1; D017466:Receptors, Endothelin; D018179:Receptors, Thrombin; D019716:Tissue Inhibitor of Metalloproteinase-2; C076213:PD 142893; D013917:Thrombin; D020778:Matrix Metalloproteinase 2