Objective: We have recently demonstrated that matrix metalloproteinase-2 (MMP-2) alters vascular function through cleavage of vasoactive peptides, resulting in increased vasoconstriction and reduced vasodilation. We, therefore, hypothesized that MMP levels are increased in women with preeclampsia. In addition, because vascular endothelial growth factor (VEGF) has been implicated in the pathophysiology of preeclampsia and is involved in angiogenesis that requires the release of proteases to allow for migration of endothelial cells, we hypothesized that VEGF increases release of MMPs from endothelial cells.
Methods: We used zymographic analysis to evaluate MMP-2/MMP-9 levels in plasma of women with preeclampsia (n=12) compared to women with uncomplicated pregnancies (n=12). In addition, we evaluated the changes in the levels of MMP-2 and MMP-9 as well as tissue inhibitors of MMPs (TIMP-1 and TIMP-2) released by cultured human umbilical vein endothelial cells in response to VEGF (0.1-10 ng/mL).
Results: Our data showed that plasma MMP-2 levels were significantly higher in women with preeclampsia compared to women with uncomplicated pregnancies (arbitrary intensity units: 690 +/-111 and 252 +/-56, respectively, p<0.05). MMP-9 levels were below the level of detection. In addition, VEGF stimulated endothelial MMP-2 and MMP-9 release in a concentration- and time-dependent (6-24 h) manner. Moreover, VEGF stimulation of MMP release occurs without significantly affecting the release of TIMP-1 and TIMP-2.
Conclusions: These data suggest that VEGF promotes secretion of MMPs from endothelial cells that, in turn, could alter vascular function in women with preeclampsia.