<br>CGRP和SP的作用以及感觉神经元与内皮细胞之间的细胞信号对话,Biological Research

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CGRP和SP的作用以及感觉神经元与内皮细胞之间的细胞信号对话
Biological Research ( IF 4.3 ) Pub Date : 2024-09-11 , DOI: 10.1186/s40659-024-00538-6
Alice Leroux ₁ , Micaela Roque ₁ , Elina Casas ₁ , Jacques Leng ₂ , Christelle Guibert _{3,

4} , Beatrice L'Azou ₁ , Hugo Oliveira ₁ , Joëlle Amédée ₁ , Bruno Paiva Dos Santos _{1,

5}

Affiliation

越来越多的证据表明感觉神经支配在骨代谢、重塑和修复中的作用，但骨中的神经血管耦合却很少被研究。使用微流体装置作为间接共培养模型来模拟体外神经支配的生理场景，我们的小组证明感觉神经元（SN）能够调节内皮细胞（EC）的细胞外基质重塑，特别是通过感觉神经肽，即降钙素基因相关肽(CGRP)和P物质(SP)。尽管如此，人们对神经血管耦合中的细胞信号通路和作用机制仍然知之甚少。在这里，为了在分子水平上表征 SN 和 EC 之间的通讯，我们评估了 SN 以及神经肽 CGRP 和 SP 对 EC 的影响。我们重点关注已知在内皮功能中发挥作用的不同途径：钙信号传导、p38 和 Erk1/2；通过 Cx43 控制信号传播；内皮细胞通过产生一氧化氮 (NO) 发挥功能。评估了 SNs 对 ECs Ca2+ 流入、Cx43 表达、内皮一氧化氮合酶 (eNOS) 和一氧化氮 (NO) 产生、p38、ERK1/2 及其磷酸化形式的影响。此外，CGRP 和 SP 的作用可以在共培养模型中使用各自的拮抗剂进行分析，或者通过直接添加到 EC 单一培养物上进行分析。我们发现辣椒素刺激的 SN 会诱导 EC 中 Ca2+ 流入增加。 SN 刺激 EC 中 NO 产生的增加，可能与抑制性 eNOS T495 磷酸化位点的减少有关。由 SN 产生的神经肽 CGRP 似乎是 EC 中这种效应的介质之一，因为在 EC 和 SN 共培养物中，在 CGRP 拮抗剂存在的情况下，NO 产生减少，而当用合成 CGRP 刺激 EC 时，NO 产生增加。综上所述，我们的结果表明 SN 通过 CGRP 产生和 NO 信号通路在控制内皮细胞功能中发挥重要作用。

"点击查看英文标题和摘要"

The effect of CGRP and SP and the cell signaling dialogue between sensory neurons and endothelial cells

Increasing evidences demonstrate the role of sensory innervation in bone metabolism, remodeling and repair, however neurovascular coupling in bone is rarely studied. Using microfluidic devices as an indirect co-culture model to mimic in vitro the physiological scenario of innervation, our group demonstrated that sensory neurons (SNs) were able to regulate the extracellular matrix remodeling by endothelial cells (ECs), in particular through sensory neuropeptides, i.e. calcitonin gene-related peptide (CGRP) and substance P (SP). Nonetheless, still little is known about the cell signaling pathways and mechanism of action in neurovascular coupling. Here, in order to characterize the communication between SNs and ECs at molecular level, we evaluated the effect of SNs and the neuropeptides CGRP and SP on ECs. We focused on different pathways known to play a role on endothelial functions: calcium signaling, p38 and Erk1/2; the control of signal propagation through Cx43; and endothelial functions through the production of nitric oxide (NO). The effect of SNs was evaluated on ECs Ca2+ influx, the expression of Cx43, endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, p38, ERK1/2 as well as their phosphorylated forms. In addition, the role of CGRP and SP were either analyzed using respective antagonists in the co-culture model, or by adding directly on the ECs monocultures. We show that capsaicin-stimulated SNs induce increased Ca2+ influx in ECs. SNs stimulate the increase of NO production in ECs, probably involving a decrease in the inhibitory eNOS T495 phosphorylation site. The neuropeptide CGRP, produced by SNs, seems to be one of the mediators of this effect in ECs since NO production is decreased in the presence of CGRP antagonist in the co-culture of ECs and SNs, and increased when ECs are stimulated with synthetic CGRP. Taken together, our results suggest that SNs play an important role in the control of the endothelial cell functions through CGRP production and NO signaling pathway.

更新日期：2024-09-11

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