α7 型烟碱型乙酰胆碱受体对含周细胞的视网膜毛细血管的调节作用。
Alpha 7-nicotinic cholinoceptor regulation of pericyte-containing retinal capillaries.
机构信息
Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Fudan University, Shanghai, 200032, China.
Eye Institute, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
出版信息
Br J Pharmacol. 2023 Sep;180(17):2196-2213. doi: 10.1111/bph.16067. Epub 2023 Apr 23.
BACKGROUND AND PURPOSE
Local blood flow regulation relies on the coordination between neurons and pericyte-containing capillaries. Pericyte relaxation and contraction are influenced by vasoactive substances and regulated by neurotransmitters. α7 nicotinic acetylcholine receptors (α7-nAChRs), involved in the regulation of vascular function and inhibitory γ-aminobutyric acid (GABA) systems, have neuroprotective effects against CNS diseases. Although α7-nAChRs are found throughout the retina, their contribution to the retinal capillary tone remains unknown. Here, we investigated the neurovascular coupling mechanism underlying α7-nAChR-mediated retinal capillary tone regulation.
EXPERIMENTAL APPROACH
Changes in capillary diameter and pericyte transverse diameter during drug perfusion were observed using differential interference contrast (DIC) microscopy, to help elucidate signalling pathways underlying α7-nAChR-mediated regulation of capillary blood flow at the whole retinal level. Patch clamp technique was used to investigate α7-nAChR-mediated regulation of the GABA synaptic circuit. Immunofluorescence was used to explore the expression of α7-nAChRs and GABA receptors.
KEY RESULTS
Activating α7-nAChRs on the endothelial cell membrane caused perinuclear accumulation of endothelial nitric oxide synthase (eNOS), resulting in dilated retinal capillaries and pericytes via the nitric oxide synthase (NOS)/nitric oxide (NO)/guanosine 3',5'- monophosphate (cGMP) signalling pathway. Neuronal α7-nAChR activation directly relaxed retinal capillaries and pericytes via a neurovascular coupling mechanism. α7-nAChR also increased the vesicular release of GABA, possibly promoting the release of NO by binding to GABA receptors in retinal ganglion cells (RGCs) and relaxing blood vessels via eNOS-NO, with GABA binding to GABA receptors on retinal capillary endothelial cells.
CONCLUSION AND IMPLICATIONS
α7-nAChR activation causes vasorelaxation of retinal capillaries.
背景与目的
局部血流调节依赖于神经元和含周细胞的毛细血管之间的协调。周细胞的舒张和收缩受血管活性物质的影响，并受神经递质的调节。α7 烟碱型乙酰胆碱受体（α7-nAChRs）参与血管功能的调节和抑制性γ-氨基丁酸（GABA）系统，对中枢神经系统疾病具有神经保护作用。尽管α7-nAChRs 存在于整个视网膜中，但它们对视网膜毛细血管张力的贡献尚不清楚。在这里，我们研究了α7-nAChR 介导的视网膜毛细血管张力调节的神经血管耦联机制。
实验方法
使用微分干涉对比（DIC）显微镜观察药物灌注过程中毛细血管直径和周细胞横向直径的变化，以帮助阐明α7-nAChR 介导的整个视网膜水平毛细血管血流调节的信号通路。采用膜片钳技术研究α7-nAChR 对 GABA 突触回路的调节作用。免疫荧光法用于研究α7-nAChRs 和 GABA 受体的表达。
主要结果
激活内皮细胞膜上的α7-nAChRs 导致内皮型一氧化氮合酶（eNOS）核周聚集，通过一氧化氮合酶（NOS）/一氧化氮（NO）/鸟苷 3'，5'-单磷酸（cGMP）信号通路导致视网膜毛细血管和周细胞扩张。神经元α7-nAChR 的激活通过神经血管耦联机制直接松弛视网膜毛细血管和周细胞。α7-nAChR 还通过与视网膜神经节细胞（RGC）上的 GABA 受体结合并通过 eNOS-NO 放松血管来增加 GABA 的囊泡释放，从而可能促进 NO 的释放，GABA 与视网膜毛细血管内皮细胞上的 GABA 受体结合。
结论和意义
α7-nAChR 的激活导致视网膜毛细血管的血管舒张。
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