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 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.
Greenaway
James
J
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada.
Lawler
Jack
J
Moorehead
Roger
R
Bornstein
Paul
P
Lamarre
Jonathan
J
Petrik
Jim
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000166:cytology / Q000378:metabolism; D010053:Ovary / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A