Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A
Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A
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DOI：
10.1172/jci26316
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发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Ambati, J
中科院分区：
文献类型：
--
作者：
Nozaki, M;Sakurai, E;Ambati, J
VEGF-A在许多组织中促进血管生成。在这里，我们报告说，脉络膜新生血管（CNV）的刺激损伤前增加过量的VEGF-A，但抑制VEGF-A损伤后。这种非正统的抗血管生成作用是通过VEGFR-1激活和VEGFR-2失活介导的，后者通过含Src同源结构域2（含SH 2）酪氨酸磷酸酶-1（SHP-1）介导。VEGFR-1特异性配体胎盘生长因子-1（PlGF-1），而不是选择性结合VEGFR-2的VEGF-E，模拟了这些反应。过量的VEGF-A增加了损伤前的CNV，因为VEGFR-1的激活被分泌的酸性和富含半胱氨酸的蛋白质（Cys）沉默。损伤后VEGF-A的瞬时下降揭示了一个时间窗口，其中VEGF-A信号主要通过VEGFR-1传递。这些观察结果表明，VEGF-A抑制的治疗设计应包括对VEGF水平和活性的考虑。
VEGF-A promotes angiogenesis in many tissues. Here we report that choroidal neovascularization (CNV) incited by injury was increased by excess VEGF-A before injury but was suppressed by VEGF-A after injury. This unorthodox antiangiogenic effect was mediated via VEGFR-1 activation and VEGFR-2 deactivation, the latter via Src homology domain 2-containing (SH2-containing) tyrosine phosphatase-1 (SHP-1). The VEGFR-1-specific ligand placental growth factor-1 (PlGF-1), but not VEGF-E, which selectively binds VEGFR-2, mimicked these responses. Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC). The transient decline of SPARC after injury revealed a temporal window in which VEGF-A signaling was routed principally through VEGFR-1. These observations indicate that therapeutic design of VEGF-A inhibition should include consideration of the level and activity of SPARC.