17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells.
Vascular remodelling occurs during all stages of atherosclerotic progression. Anti-atherosclerotic drugs may function by restoring regulation of the processes involved in remodelling of the extracellular matrix. A key group of enzymes involved in these processes are the matrix metalloproteinases (MMPs). Oestrogens have been demonstrated to possess anti-atherosclerotic properties at low concentrations while being associated with lesion formation at high concentrations. We examined the effect of 17beta-oestradiol on MMP-2 expression in human coronary artery (CAVSMC) and umbilical artery vascular smooth muscle cells (UAVSMC). MMP-2 expression was measured by chemiluminescent immunoblotting and quantified by laser densitometry. pro-MMP-2 was secreted by VSMCs and increasing levels of 17beta-oestradiol, from physiological through supraphysiological, were associated with significant dose-dependent increases in MMP-2 levels in culture media. This effect was dependent on de novo protein synthesis and could be antagonised by the oestrogen receptor antagonist, tamoxifen, and the specific receptor antagonist ICI 182, 780. 17beta-Oestradiol appears to be a specific stimulator of MMP-2 release from human vascular cells. The concentration dependence of this effect suggests a basis for the differential effects of low and high oestrogen levels on vascular integrity.
Wingrove
C S
CS
Wynn Department of Metabolic Medicine, Division of Medicine, Imperial College School of Medicine, 21 Wellington Rd., London NW8 9SQ, UK. c.wingrove@ic.ac.uk
Garr
E
E
Godsland
I F
IF
Stevenson
J C
JC
D001161:Arteriosclerosis / Q000209:etiology; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D018093:Gelatinases / Q000096:biosynthesis*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D013629:Tamoxifen / Q000494:pharmacology; D014469:Umbilical Arteries / Q000166:cytology
D004965:Estrogen Antagonists; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2