The Effects of Preeclampsia and Oxygen Environment on Endothelial Release of Matrix Metalloproteinase‐2

Abstract

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.