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Am J Physiol Heart Circ Physiol 278: H1473-H1479, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 5, H1473-H1479, May 2000

Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries

Carlos Fernandez-Patron1, Marek W. Radomski2, and Sandra T. Davidge1

1 Perinatal Research Centre, Departments of Obstetrics/Gynaecology and Physiology, University of Alberta, Edmonton, Alberta T6G 2S2; and 2 Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

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-NH2), 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.

endothelin; vascular; injury; nitric oxide; prostaglandins


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