Peripheral nerve injury has been suggested to up-regulate mRNA for the vascular endothelial growth factor (VEGF) which enhances nerve regeneration. VEGF is known to regulate angiogenesis by binding with a specific receptor, the vascular endothelial growth factor receptor (VEGFR). However, little is known about the involvement of VEGF-VEGFR signaling in the nerve regeneration at early stages though previous studies contained a lengthy observation. The present study examined that relationship between angiogenesis and peripheral nerve regeneration at the early stage after nerve transection by focusing on the chronological changes in the expression patterns of VEGF-VEGFR signaling. This study used our previously reported experimental model for nerve regeneration following the transection of the inferior alveolar nerve (IAN) in mice. In a double staining of PGP9.5 and CD31, respective markers for the nerve fibers and endothelial cells, CD31 immunoreactions first appeared in the injury site on postoperative (PO) day 2 when the transected nerve fibers had not been re-connected. The most intense immunoreaction for CD31 was found around the regenerating nerve fibers extending from the proximal stump on PO day 3, but it gradually lessened to disappear by PO day 7. The expression patterns of VEGFR1 and VEGFR2 showed similar chronological changes through the observation periods, with most intense immunoreaction found on PO day 3. Western blotting of total protein extracted from the injury site demonstrated the clear bands for VEGF-A and VEGF-B on PO day 2, indicating a time lag for the expression of ligands and receptors. A local administration of antibody to VEGF-A inhibited the elongation of the nerve fibers from the proximal stump. Furthermore, this administration of VEGF-A antibody inhibited the expression of CD31 in the gap between proximal and distal stumps. These results indicated that a nerve injury initiates productions in VEGF-A and VEFG-B, followed with the expression of VEGFR1 and VEGFR2 at early stages after the nerve injury. Taken these findings together, it is reasonable to postulate that immediate response of VEGF-VEGFR signaling to nerve injury plays a crucial role in local angiogenesis, resulting in a trigger for the regeneration of the nerve fibers in mouse IAN.

中文翻译：

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通过激活VEGF-VEGFR信号进行血管化对于周围神经再生至关重要。

周围神经损伤已被建议上调血管内皮生长因子（VEGF）的mRNA，从而增强神经再生。已知VEGF通过与特定受体血管内皮生长因子受体（VEGFR）结合来调节血管生成。但是，关于VEGF-VEGFR信号在早期神经再生中的作用知之甚少，尽管先前的研究包含了漫长的观察。本研究通过关注VEGF-VEGFR信号表达模式的时间变化，研究了神经横断后早期血管新生与周围神经再生之间的关系。这项研究使用了我们先前报道的小鼠下牙槽神经（IAN）横切后神经再生的实验模型。在PGP9.5和CD31的双重染色中，分别标记了神经纤维和内皮细胞，CD31免疫反应首先在术后（PO）第2天的损伤部位出现，当时未切断横切的神经纤维。在PO第3天从近端残端延伸的再生神经纤维周围发现了CD31的最强免疫反应，但到PO第7天逐渐减少，消失了。在观察期间，VEGFR1和VEGFR2的表达模式显示出类似的时间变化，在PO第3天发现最强烈的免疫反应。从损伤部位提取的总蛋白的Western印迹显示在PO第2天，VEGF-A和VEGF-B的条带清晰，表明配体和受体的表达存在时滞。局部施用针对VEGF-A的抗体抑制了来自近端残端的神经纤维的伸长。此外，这种VEGF-A抗体的施用抑制了近端和远端残端之间的间隙中CD31的表达。这些结果表明，神经损伤开始在VEGF-A和VEFG-B中产生，随后在神经损伤后的早期表达VEGFR1和VEGFR2。综合这些发现，可以合理地推测VEGF-VEGFR信号对神经损伤的即时反应在局部血管生成中起着至关重要的作用，从而导致了小鼠IAN神经纤维再生的触发因素。这些结果表明，神经损伤开始在VEGF-A和VEFG-B中产生，随后在神经损伤后的早期表达VEGFR1和VEGFR2。综合这些发现，可以合理地推测VEGF-VEGFR信号对神经损伤的即时反应在局部血管生成中起着至关重要的作用，从而导致了小鼠IAN神经纤维再生的触发因素。这些结果表明，神经损伤开始在VEGF-A和VEFG-B中产生，随后在神经损伤后的早期表达VEGFR1和VEGFR2。综合这些发现，可以合理地推测VEGF-VEGFR信号对神经损伤的即时反应在局部血管生成中起着至关重要的作用，从而导致了小鼠IAN神经纤维再生的触发因素。