Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1)
Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1)
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DOI：
10.1002/jcp.20904
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发表时间：
2007-03-01
影响因子：
5.6
通讯作者：
Petrik, Jim
中科院分区：
文献类型：
--
作者：
Greenaway, James;Lawler, Jack;Petrik, Jim
VEGF 是一种有效的促血管生成因子，其作用与许多抗血管生成蛋白相反，包括血小板反应蛋白-1 (TSP-1)。我们之前已经证明 VEGF 在卵巢中具有重要的血管外作用，并且 VEGF 和 TSP-1 在整个卵巢周期中呈反向表达。然而，迄今为止，TSP-1 和 VEGF 之间的因果相互作用尚未确定。在这里，我们证明 TSP-1 通过结合生长因子并通过 LRP-1 将其内化，对 VEGF 具有直接抑制作用。缺乏 TSP-1 的小鼠生育力低下，并表现出卵巢血管过多和卵巢形态改变。用 TSP-1 处理卵巢细胞可降低 VEGF 水平，并使细胞更容易受到 TNI α 诱导的细胞凋亡的影响。通过 RNA 干扰敲低 TSP-1，导致 VEGF 过度表达并减少细胞因子诱导的细胞凋亡。总之，我们证明了 TSP-1 对卵巢中 VEGF 的直接抑制作用。 TSP-1 对 VEGF 的调节似乎是卵巢血管生成和卵泡发育的重要介质。
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.