Angiogenesis plays a key role in bone regeneration. The role of neurons of peripheral nerves involved in angiogenesis of bone defects needs to be explored. The transient receptor potential vanilloid 1 (TRPV1), a nociceptor of noxious stimuli, is expressed on sensory neurons. Apart from nociception, little is known about the role of sensory innervation in angiogenesis. Calcitonin gene-related peptide (CGRP), a neuropeptide secreted by sensory nerve terminals, has been associated with vascular regeneration. We characterized the reinnervation of vessels in bone repair and assessed the impact of TRPV1-CGRP signaling on early vascularization. We investigated the pro-angiogenic effect of neuronal TRPV1 in the mouse model of femur defect. Micro-CT analysis with Microfil® reagent perfusion demonstrated neuronal TRPV1 activation enhanced angiogenesis by increasing vessel volume, number, and thickness. Meanwhile, TRPV1 activation upregulated the mRNA and protein expression of vascular endothelial growth factor A (VEGF-A), cell adhesion molecule-1 (CD31), and CGRP. Immunostaining revealed the co-localization of TRPV1 and CGRP in dorsal root ganglia (DRG) sensory neurons. By affecting neuronal TRPV1 channels, the release of neuronal and local CGRP was controlled. We demonstrated that TRPV1 influenced on blood vessel development by promoting CGRP release from sensory nerve terminals. Our results showed that neuronal TRPV1 played a crucial role in regulating angiogenesis during bone repair and provided important clinical implications for the development of novel therapeutic approaches for angiogenesis.

中文翻译：

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感觉神经元瞬时受体电位vanilloid-1通道通过CGRP调节体内血管生成

血管生成在骨再生中起着关键作用。需要探索参与骨缺损血管生成的周围神经元的作用。瞬时感受器电位香草酸 1 (TRPV1) 是一种有害刺激的伤害感受器，在感觉神经元上表达。除了伤害感受之外，人们对感觉神经支配在血管生成中的作用知之甚少。降钙素基因相关肽（CGRP）是一种由感觉神经末梢分泌的神经肽，与血管再生有关。我们描述了骨修复中血管神经支配的特征，并评估了 TRPV1-CGRP 信号传导对早期血管化的影响。我们研究了神经元 TRPV1 在股骨缺损小鼠模型中的促血管生成作用。使用 Microfil 进行显微 CT 分析®试剂灌注证明神经元 TRPV1 激活通过增加血管体积、数量和厚度来增强血管生成。同时，TRPV1 激活上调血管内皮生长因子 A (VEGF-A)、细胞粘附分子-1 (CD31) 和 CGRP 的 mRNA 和蛋白表达。免疫染色揭示了背根神经节 (DRG) 感觉神经元中 TRPV1 和 CGRP 的共定位。通过影响神经元 TRPV1 通道，控制神经元和局部 CGRP 的释放。我们证明 TRPV1 通过促进感觉神经末梢释放 CGRP 来影响血管发育。我们的研究结果表明，神经元 TRPV1 在骨修复过程中调节血管生成中发挥着至关重要的作用，并为血管生成新治疗方法的开发提供了重要的临床意义。