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

J Cell Physiol. 2007 Mar;210(3):807-18. doi: 10.1002/jcp.20904.

Abstract

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 TNFalpha-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CHO Cells
  • Cell Line
  • Cell Proliferation
  • Cricetinae
  • Cricetulus
  • Female
  • Gene Expression Regulation
  • Granulosa Cells / cytology
  • Granulosa Cells / metabolism
  • Mice
  • Mice, Knockout
  • Ovarian Follicle / cytology
  • Ovarian Follicle / metabolism
  • Ovary / blood supply
  • Ovary / cytology
  • Ovary / metabolism*
  • Protein Binding
  • RNA Interference
  • Rats
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Lrp1 protein, mouse
  • Receptors, LDL
  • Thrombospondin 1
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A