Abstract：
BACKGROUND: 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.
OBJECTIVE: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：交感神经支配在调节血管平滑肌细胞（VSMC）表型和血管疾病中起重要作用，但其在腹主动脉瘤（AAA）中的作用尚不清楚。
目的：本研究旨在探讨交感神经支配在促进AAA发展中的作用及其潜在机制。
方法：采用蛋白质印迹和免疫化学染色检测交感神经支配过度。我们通过腹腔神经节切除术（CGX）和6-OHDA给药进行了交感神经支配，以了解交感神经支配在AAA中的作用，并通过转录组和功能研究研究了潜在的机制。利用Sema4D敲除(Sema4D-/-)小鼠来确定Sema4D在诱导交感神经支配过度和AAA发育中的参与。
结果：我们观察到交感神经支配过度，交感神经重塑最重要的形式，在小鼠AAA模型和AAA患者中。CGX或6-OHDA消除交感神经支配能显著抑制AAA的发展和进展。我们进一步揭示了交感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测序显示，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神经支配过度。我们一致观察到在Sema4D缺陷小鼠中AAA进展显著改善。
结论：由破骨细胞样细胞来源的Sema4D驱动的交感神经支配通过激活eATP/P2rx4/p38通路促进VSMC表型转换并加速病理性动脉瘤进展。抑制交感神经支配过度是预防和治疗AAA的潜在新治疗策略。
目的：本研究旨在探讨交感神经支配在促进AAA发展中的作用及其潜在机制。
方法：采用蛋白质印迹和免疫化学染色检测交感神经支配过度。我们通过腹腔神经节切除术（CGX）和6-OHDA给药进行了交感神经支配，以了解交感神经支配在AAA中的作用，并通过转录组和功能研究研究了潜在的机制。利用Sema4D敲除(Sema4D-/-)小鼠来确定Sema4D在诱导交感神经支配过度和AAA发育中的参与。
结果：我们观察到交感神经支配过度，交感神经重塑最重要的形式，在小鼠AAA模型和AAA患者中。CGX或6-OHDA消除交感神经支配能显著抑制AAA的发展和进展。我们进一步揭示了交感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测序显示，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神经支配过度。我们一致观察到在Sema4D缺陷小鼠中AAA进展显著改善。
结论：由破骨细胞样细胞来源的Sema4D驱动的交感神经支配通过激活eATP/P2rx4/p38通路促进VSMC表型转换并加速病理性动脉瘤进展。抑制交感神经支配过度是预防和治疗AAA的潜在新治疗策略。
