© 2000 American Heart Association, Inc.
Integrative Physiology |
Vascular Matrix Metalloproteinase-2–Dependent Cleavage of Calcitonin Gene-Related Peptide Promotes Vasoconstriction
From the Perinatal Research Centre, Departments of Obstetrics/Gynaecology and Physiology (C.F.-P., K.G.S., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; Department of Biosciences, Division of Biochemistry (E.K.), University of Helsinki, Finland; and Department of Pharmacology (M.W.R.), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Carlos Fernandez-Patron and Sandra T. Davidge, Perinatal Research Centre, 232 HMRC, Departments of Obstetrics/Gynaecology and Physiology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail cf2@ualberta.ca and sandra.davidge{at}ualberta.ca
Abstract—Matrix metalloproteinase (MMP)-2 has been historically associated with the process of vascular remodeling through the cleavage of extracellular matrix proteins. However, we recently found that MMP-2 also cleaves the endothelium-derived peptide big endothelin-1, ET-1[1–38] and yields the novel vasoconstrictor ET-1[1–32]. We therefore investigated the effects of MMP-2 inhibitors as potential vasodilators. MMP inhibition with ortho-phenanthroline (0.3 to 30 µmol/L) induced vasorelaxation of isolated rat mesenteric arteries (maximum of relaxation=74.5±27.6% at 30 µmol/L). However, phosphoramidon (0.3 to 30 µmol/L), which inhibits some metalloenzymes, but not MMP-2, did not dilate the arteries. Selective inhibition of endogenous MMP-2 with the novel tissue-permeable cyclic peptide CTTHWGFTLC (CTT, 10 µmol/L) also caused vasorelaxation (by 85±6%), whereas STTHWGFTLS (10 µmol/L), an inactive CTT analogue, did not dilate the arteries. Interestingly, the vasorelaxation that results from MMP-2 inhibition was endothelium-independent. Thus, we examined whether MMP-2 acted on peptides derived from the smooth muscle or the perivascular nerves. Recombinant human MMP-2 cleaved calcitonin gene-related peptide (CGRP) specifically at the Gly14-Leu15 peptide bond and reduced the vasodilatory potency of CGRP by 20-fold. Inhibition of MMP-2 increased the amount of intact CGRP in arteries and enhanced vasorelaxation induced by anandamide, which stimulates CGRP release. Vasorelaxation in response to MMP-2 inhibition was abolished by CGRP[8–37], a selective CGRP receptor antagonist, and by capsaicin, which depletes arterial perivascular nerves of CGRP. We conclude that vascular MMP-2 cleaves endogenous CGRP and promotes vasoconstriction. These data suggest a novel mechanism of regulating the vasoactive and, possibly, the neurohormonal actions of CGRP and establish MMP-2 as a modulator of vascular function.
Key Words: vascular • matrix metalloproteinase • calcitonin gene-related peptide
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