Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown. This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved. Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development. We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice. Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.

中文翻译：

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交感神经过度支配通过促进血管平滑肌细胞表型转换来驱动腹主动脉瘤的发展


交感神经过度神经支配在调节血管平滑肌细胞（VSMC）表型和血管疾病中发挥着重要作用，但其在腹主动脉瘤（AAA）中的作用仍不清楚。本研究旨在探讨交感神经过度神经支配在促进 AAA 发展中的作用及其潜在机制。使用蛋白质印迹和免疫化学染色来检测交感神经过度神经支配。我们通过腹腔神经节切除术 (CGX) 和 6-OHDA 给药进行去交感神经支配，以了解交感神经过度支配在 AAA 中的作用，并通过转录组和功能研究研究其潜在机制。利用 Sema4D 敲除 (Sema4D) 小鼠来确定 Sema4D 在诱导交感神经过度支配和 AAA 发育中的作用。我们在小鼠 AAA 模型和 AAA 患者中观察到交感神经过度神经支配，这是交感神经重塑的最重要形式。通过 CGX 或 6-OHDA 消除交感神经过度支配可显着抑制 AAA 的发生和进展。我们进一步揭示，交感神经过度神经支配通过释放细胞外 ATP (eATP) 和激活 eATP-P2rx4-p38 信号传导促进 AAA 中的 VSMC 表型转换。此外，单细胞RNA测序表明，破骨细胞样细胞分泌的Sema4D通过与Plxnb1结合诱导交感神经扩散和过度神经支配。我们一致观察到 Sema4D 缺陷小鼠的 AAA 进展显着改善。由破骨细胞样细胞衍生的 Sema4D 驱动的交感神经过度支配可通过激活 eATP/P2rx4/p38 途径促进 VSMC 表型转换并加速病理性动脉瘤进展。 抑制交感神经过度神经支配成为预防和治疗 AAA 的潜在新治疗策略。