VEGF-A165b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in Vivo and in Vitro
VEGF-A165b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in Vivo and in Vitro
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DOI：
10.1016/j.ajpath.2013.05.031
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发表时间：
2013-09-01
影响因子：
6
通讯作者：
Donaldson, Lucy F.
中科院分区：
文献类型：
--
作者：
Beazley-Long, Nicholas;Hua, Jing;Donaldson, Lucy F.
血管内皮生长因子（VEGF）A通过选择性RNA剪接产生为两个同种型家族，由VEGF-A（165）a和VEGF-A（165）B表示。这些亚型对血管通透性、血管生成和血管舒张具有相反的作用。促血管生成VEGF-A（165）α亚型在海马、背根神经节和视网膜神经元中具有神经保护作用，但其适当性、血管扩张和血管生成特性限制了其治疗用途。相反，内源性VEGF-A（165）B对神经元的神经保护作用对于神经退行性病变是有利的。在海马和皮质神经元中检测到人和大鼠VEGF-A（165）B的内源性表达。VEGF-A（165）B在大鼠脑中占总VEGF-A的显著比例。重组人VEGF-A（165）B b对多种损伤具有神经保护作用，包括海马神经元的神经元兴奋毒性、化疗诱导的背根神经节神经元细胞毒性和体内大鼠视网膜缺血-再灌注损伤中的视网膜神经节细胞（RGC）。神经保护作用依赖于VEGFR 2和MEK 1/2的激活，但不依赖于p38或磷脂酰肌醇3激酶的激活。重组人VEGF-A（165）B是一种有效的神经保护剂。在体内和体外通过VEGFR 2、MEK 1/2和抑制半胱天冬酶-3诱导来保护外周和中枢神经元。VEGF-A（165）B可用于治疗涉及神经元损伤的病理，包括海马神经变性、青光眼、糖尿病性视网膜病变和周围神经病变。VEGF-A（165）B表达的内源性性质表明，VEGF-A的非同种型特异性抑制（出于抗血管生成的原因）可能损害视网膜和感觉神经元。
Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A(165)a and VEGF-A(165)b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A(165)a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeabitity, vaso-dilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A(165)b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A(165)b was detected in hippocampal and cortical neurons. VEGF-A(165)b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A(165)b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3 kinase activation. Recombinant human VEGF-A(165)b is a neuroprotective agent that effectively. protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A(165)b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A(165)b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.