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

The vasodilator effects of thrombin depend on activation of proteinase-acti vated receptor (PAR)-1 and the subsequent release of endothelin (ET)-1, whi ch stimulates the generation of nitric oxide and PGs. We recently showed th at thrombin released matrix metalloproteinase-2 (MMP-2) from rat arteries. We have now studied the significance of this release for the vasodilator ef fects of thrombin. Thrombin (greater than or equal to 100 pmol), but not a PAR-1-activating peptide (TFLLR-NH2), produced a long-lasting (> 10 min) va sorelaxation of rat mesenteric arteries, as detected by a microperfusion bi oassay. Thrombin induced a simultaneous release of vascular MMP-2 into arte rial 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 vasore laxation. These vasodilatory effects of thrombin and MMP-2 were significant ly (P < 0.05) inhibited by endothelium denudation and by PD-142893 (2 nmol) , an antagonist of ET receptors. Furthermore, both thrombin and MMP-2 const ricted endothelium-denuded arteries. These results show that the vasodilato r effects of thrombin may depend, in part, on a release of vascular MMP-8 a nd downstream activation of ETs. Thus MMP-2-dependent signaling may complem ent the PAR-1-dependent pathway of vasodilator action of thrombin.