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

被引:143
作者
Greenaway, James
Lawler, Jack
Moorehead, Roger
Bornstein, Paul
Lamarre, Jonathan
Petrik, Jim [1 ]
机构
[1] Univ Guelph, Dept Biomed Sci, Guelph, ON N1G 2W1, Canada
[2] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA
[3] Harvard Univ, Sch Med, Boston, MA 02215 USA
[4] Univ Washington, Dept Biochem & Med, Seattle, WA 98195 USA
关键词
D O I
10.1002/jcp.20904
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 TNI alpha-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 bean important mediator of ovarian angiogenesis and follicle development.
引用
收藏
页码:807 / 818
页数:12
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