© 1999 American Heart Association, Inc.
Molecular Medicine |
Vascular Matrix Metalloproteinase-2 Cleaves Big Endothelin-1 Yielding a Novel Vasoconstrictor
From the Perinatal Research Centre (C.F-P., S.T.D.), Departments of Obstetrics/Gynaecology and Physiology, University of Alberta, Edmonton, Alberta, Canada and the Department of Pharmacology (M.W.R), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Sandra T. Davidge, Perinatal Research Centre, 232 HMRC, Departments of Obstetrics/Gynaecology and Physiology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail sandra.davidge{at}ualberta.ca
Abstract—Matrix metalloproteinase-2 (MMP-2, gelatinase A) and its tissue inhibitor (TIMP-2) are mainly known for their roles in the (patho)physiological remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. A mechanism of action of MMP-2 is the proteolytic breakdown of specific extracellular matrix proteins. The amino acid sequences in interstitial collagen (Gly-Leu/Ile) and laminin-5 (Ala-Leu) that are cleaved by MMP-2 are homologous to a region (Gly32-Leu33) within human big endothelin-1[1 to 38] (big ET-1). Big ET-1 requires cleavage to an active form to produce vasoconstriction. We tested the hypothesis that vascular MMP-2 can cleave big ET-1, thus generating a vasoconstrictor peptide. In perfused rat mesenteric arteries with an intact endothelium, inhibition of vascular MMP-2 with TIMP-2 reduced (by 16.2±4.2%) the vasoconstrictor effects of big ET-1 (50 pmol). However, when the endothelium was mechanically removed, TIMP-2 abolished (>90%) the vasoconstriction of big ET-1, and this effect was mimicked by an anti–MMP-2 antibody. Incubation of big ET-1 with recombinant human MMP-2 resulted in the specific cleavage of the Gly32-Leu33 bond of big ET-1. Moreover, the resultant peptide ET-1[1 to 32] exerted greater vasoconstrictor effects than big ET-1. We conclude that vascular MMP-2 contributes to the vasoconstrictor effects of big ET-1 by cleaving big ET-1 to yield a novel and potent vasoconstrictor, ET-1[1 to 32]. These data implicate, for the first time, the endogenous MMP-2/TIMP-2 system in the regulation of vascular reactivity.
Key Words: metalloproteinase • endothelin • vasculature
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