Nafoxidine modulates the expression of matrix-metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in endothelial cells

During angiogenesis, proteases and their inhibitors interact in the remodel ling of the basement membrane. It has been demonstrated that nafoxidine has antiangiogenic activity in the chick egg chorioallantoic membrane assay, b ut the precise mechanism of action is unknown. We have analyzed the effect Of the partial estrogen antagonist nafoxidine on human umbilical vein endot helial cells (HUVEC). Our data indicated that in nafoxidine-treated endothe lial cells MMP-2 was activated. Nafoxidine upregulated, in a dose-dependent manner, the secretion of a 66 kDa TIMP-1 dimer, that lacks anti-MMP activi ty and inhibited angiogenesis in the endothelial cord formation assay. We c an postulate that nafoxidine induces an increase in TIMP-1, which has antia ngiogenic activity in the late stages of tube formation, independent of ifs capacity to inhibit MMPs.