Regulation of soluble vascular endothelial growth factor receptor 1 secretion from human endothelial cells by tissue inhibitor of metalloproteinase 1.

Vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-1) are key regulators in human ovarian angiogenesis. Produced by granulosa and ovarian theca interna cells, VEGF promotes blood vessel growth during follicular development and corpus luteum formation, whereas sVEGFR-1, which is secreted by endothelial cells, functions as an antagonist to VEGF activity by binding it. In order to gain further insights into the regulatory mechanisms of ovarian angiogenesis, the aim of the present study was to analyze the influence of tissue inhibitor of metalloproteinase 1 (TIMP-1), which is actively involved in the degradation and remodeling of the extracellular matrix, on sVEGFR-1 secretion of cultured human umbilical vein endothelial cells. sVEGFR-1 production was determined in the culture supernatant by Sandwich-ELISA. We showed that TIMP-1 produced by human granulosa cells and recombinant human TIMP-1 both significantly increased the production of sVEGFR-1 in endothelial cells. Also, the down-regulation of TIMP-1 expression by RNA interference resulted in a significant reduction of endothelial sVEGFR-1 secretion into the culture medium. Furthermore, TIMP-1 weakly inhibited proliferation of VEGF-stimulated endothelial cells. In conclusion, our results provide evidence that TIMP-1 increases the production of sVEGFR-1 in endothelial cells and thus may reduce VEGF bioavailability, leading to reduced blood vessel growth in the ovary.