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 releas e of matrix metalloproteinases (MMPs) and tissue inhibitors of metallo proteinases (TIMPs) from human dermal microvascular endothelial cells. Treatment of cultures with 10 ng/ml or more of VEGF significantly inc reased cell proliferation. The effect of VEGF treatment on the levels of specific MMPs and TIMPs in the media was subsequently examined in c ultures that were treated with 10 ng/ml VEGF. Zymography and Western b lot analyses demonstrated that gelatinase A levels in the media were i ncreased 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 conf irmed that VEGF treatment significantly increased gelatinase A levels but did not significantly increase collagenase levels. Western blot an d ELISA data showed that VEGF treatment significantly decreased TIMP-1 and TIMP-2 levels compared to untreated cultures. The data suggest th at VEGF may modulate endothelial cell-derived MMP activity by: (1) inc reasing the abundance of gelatinase A; (2) disinhibiting gelatinase A by decreasing the abundance of TIMP-2; and (3) disinhibiting preexisti ng collagenase by reducing levels of TIMP-1. These actions could contr ibute to the ability of VEGF to promote endothelial cell invasion of n ew territory. (C) 1998 Academic Press.