The effects of preeclampsia and oxygen environment on endothelial release of matrix metalloproteinase-2.
BACKGROUND
There is evidence of altered vascular endothelial function in women with preeclampsia as well as in the endothelial cells from umbilical vessels of preeclamptic pregnancies. Matrix metalloproteinase (MMP)-2 is elevated in the plasma of preeclamptic women and is a mediator of vascular reactivity; however, whether MMP-2 release is altered in preeclamptic endothelial cells is unknown. We hypothesize that MMP-2 release is enhanced in endothelial cells from preeclamptic compared with uncomplicated pregnancies and that this phenomenon may be mediated by an oxygen-dependent mechanism. Our specific hypothesis is that cells from normal pregnancies will demonstrate enhanced MMP-2 release at low oxygen (< 0.5%, 2%) compared to high oxygen (20%), thus mimicking the behavior of preeclamptic cells.


METHODS
Human umbilical vein endothelial cells (HUVECs) from preeclamptic pregnancies (n = 4) and normal pregnancies (n = 4) were incubated for 12 hr in standard culture conditions (20% oxygen). In a separate series of experiments, HUVECs from normal pregnancies (n = 6) were incubated for 12 hr at < 0.5%, 2%, and 20% oxygen. Supernatants were analyzed for MMP-2 and tissue inhibitors of metalloproteinases (TIMP)-1 and -2.


RESULTS
The HUVECs from women with preeclampsia demonstrated significantly enhanced release of MMP-2 (p < 0.05), TIMP-1 (p < 0.001), and TIMP-2 (p = 0.01) compared to normal cells. MMP-2 release from HUVECs from uncomplicated pregnancies was significantly elevated at 2% oxygen compared to < 0.5% and 20% oxygen (p < 0.05). TIMP-1 and -2 secretion was not altered with varying oxygen.


CONCLUSIONS
Preeclamptic endothelial cells demonstrate significantly enhanced MMP-2, TIMP-1 and TIMP-2 release compared to normal cells. Our data show that there are significant effects of oxygen tension on MMP-2 release from normal cells; however, the magnitude of the enhanced release is small when compared to the differences in MMP-2 release in cells from preeclamptic and normal pregnancies. Furthermore, TIMP-1 and -2 release is not affected by changes in oxygen. It is unlikely that oxygen is a key mediator of the enhanced MMP-2, TIMP-1 and TIMP-2 release observed in preeclamptic cells.
Merchant
Shaila J
SJ
Department of Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Canada.
Narumiya
Hisao
H
Zhang
Yunlong
Y
Guilbert
Larry J
LJ
Davidge
Sandra T
ST
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008429:Maternal Welfare; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010100:Oxygen