Vascular Matrix Metalloproteinase-2–Dependent Cleavage of Calcitonin Gene-Related Peptide Promotes Vasoconstriction
作者:
Carlos Fernandez-Patron,
Ken Stewart,
Yunlong Zhang,
Erkki Koivunen,
Marek Radomski,
Sandra Davidge,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2000)
卷期:
Volume 87,
issue 8
页码: 670-676
ISSN:0009-7330
年代: 2000
出版商: OVID
关键词: vascular;matrix metalloproteinase;calcitonin gene-related peptide
数据来源: OVID
摘要:
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 &mgr;mol/L) induced vasorelaxation of isolated rat mesenteric arteries (maximum of relaxation=74.5±27.6% at 30 &mgr;mol/L). However, phosphoramidon (0.3 to 30 &mgr;mol/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 &mgr;mol/L) also caused vasorelaxation (by 85±6%), whereas STTHWGFTLS (10 &mgr;mol/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-Leu15peptide 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.
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