Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1)

VEGF is a potent pro‐angiogenic factor whose effects are opposed by a host of anti‐angiogenic proteins, including thrombospondin‐1 (TSP‐1). We have previously shown that VEGF has important extravascular roles in the ovary and that VEGF and TSP‐1 are inversely expressed throughout the ovarian cycle. To date, however, a causal interaction between TSP‐1 and VEGF has not been identified. Here, we show that TSP‐1 has a direct inhibitory effect on VEGF by binding the growth factor and internalizing it via LRP‐1. Mice lacking TSP‐1 are subfertile and exhibited ovarian hypervascularization and altered ovarian morphology. Treatment of ovarian cells with TSP‐1 decreased VEGF levels and rendered the cells more susceptible to TNFα‐induced apoptosis. Knockdown of TSP‐1, through RNA interference, resulted in overexpression of VEGF and reduced cytokine‐induced apoptosis. In conclusion, we demonstrate a direct inhibitory effect of TSP‐1 on VEGF in the ovary. TSP‐1's regulation of VEGF appears to be an important mediator of ovarian angiogenesis and follicle development. J. Cell. Physiol. 210: 807–818, 2007. © 2006 Wiley‐Liss, Inc.