Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor
Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor
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DOI：
10.1182/blood-2007-08-110205
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发表时间：
2008-03-01
期刊：
影响因子：
20.3
通讯作者：
Cheresh, David A.
中科院分区：
文献类型：
--
作者：
Acevedo, Lisette M.;Barillas, Samuel;Cheresh, David A.
信号蛋白3A （Sema3A）是一种已知的轴突发芽抑制剂，也会改变血管模式。本研究表明，Sema3A在体内选择性地干扰VEGF诱导的血管生成，但不干扰bfgf诱导的血管生成。与此一致的是，Sema3A破坏了vegf介导的内皮细胞向FAK和Src的信号传导，而不是bfgf介导的FAK和Src， FAK和Src是整合素和生长因子信号传导的关键介质；然而，任何一种生长因子对ERK的信号传导均未受干扰。由于VEGF也是一种血管通透性（VP）因子，我们检测了Sema3A在VEGF介导的小鼠VP中的作用。令人惊讶的是，Sema3A不仅刺激VEGF介导的VP，而且在没有VEGF的情况下也能诱导VP。sema3a介导的VP在表达内皮神经素-1 （Nrp-1）条件缺失的成年小鼠或在系统使用功能阻断Nrp-1抗体处理的野生型小鼠中均被抑制。虽然Sema3A-和VEGF诱导的VP都依赖于Nrp-1，但它们使用不同的下游效应物，因为VEGF而不是Sema3A诱导的VP需要Src激酶信号传导。这些发现确定了Sema3A作为vegf介导的血管生成的选择性抑制剂和VP的有效诱导剂的新作用。
Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF-but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.