Vascular endothelial growth factor increases release of gelatinase a and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro

The present study was designed to determine the influences of vascular endothelial growth factor (VEGF) on cell proliferation and the release of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from human dermal microvascular endothelial cells. Treatment of cultures with 10 ng/ml or more of VEGF significantly increased cell proliferation. The effect of VEGF treatment on the levels of specific MMPs and TIMPs in the media was subsequently examined in cultures that were treated with 10 ng/ml VEGF. Zymography and Western blot analyses demonstrated that gelatinase A levels in the media were increased by VEGF treatment. Collagenase was detected by Western blots in both VEGF-treated and untreated culture media, but the levels were not significantly increased by the VEGF treatment. An ELISA assay confirmed that VEGF treatment significantly increased gelatinase A levels but did not significantly increase collagenase levels. Western blot and ELISA data showed that VEGF treatment significantly decreased TIMP-1 and TIMP-2 levels compared to untreated cultures. The data suggest that VEGF may modulate endothelial cell-derived MMP activity by: (1) increasing the abundance of gelatinase A; (2) disinhibiting gelatinase A by decreasing the abundance of TIMP-2; and (3) disinhibiting preexisting collagenase by reducing levels of TIMP-1. These actions could contribute to the ability of VEGF to promote endothelial cell invasion of new territory. (C) 1998 Academic Press.