Phosphodiesterase 5 inactivation in vascular smooth muscle cells aggravates aortic aneurysm and dissection.

IF 5.6 2区 医学 Q1 ONCOLOGY
Yuyao Feng, Yunfei Xue, Xiaohang Feng, Zhiwei Li, Luxia Ren, Wenjun Guo, Yangfeng Hou, Ting Shu, Wensi Zhang, Yang Yang, Yitian Zhou, Kai Song, Jiang Xiong, Bao Liu, Jing Wang, Hongmei Zhao
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Abstract

Aortic aneurysm and dissection (AAD) are vascular disorders with high mortality. Previous evidence has suggested an elevated risk of AAD associated with the use of phosphodiesterase 5A (PDE5A) inhibitors. PDE5A, a cGMP-hydrolyzing enzyme, is enriched in vascular smooth muscle cells (SMCs), but the role of SMC-specific PDE5A in the pathogenesis of AAD is still unclear. In this study, PDE5A expression in human and mouse aortic tissues was analyzed by single-cell RNA sequencing (scRNA-seq), western blotting, immunofluorescence, and immunohistochemistry staining. SMC-specific PDE5A knockout (PDE5ASMC-/-) and PDE5A-overexpressing (PDE5ASMC-OE) mice were constructed and utilized, along with an AAD mouse model induced by a high-fat diet and angiotensin II (Ang II) infusion. In vivo imaging and histological analyses were performed to assess aortic pathologies. PDE5A expression was reduced in human and mouse AAD aortic tissues, primarily in SMCs. Pharmacological inhibition or genetic knockout of PDE5A in SMCs exacerbated aortic wall dilatation and elastin fiber degradation, increasing AAD incidence. In contrast, the AAD phenotype was rescued in challenged PDE5ASMC-OE mice. Mechanistically, PDE5A expression influenced myosin light chain (MLC) phosphorylation, a key regulator of SMC contractility. In AAD tissues from PDE5ASMC-/- mice, increased cGMP-dependent protein kinase (PKG) activation and decreased MLC phosphorylation indicate enhanced aortic relaxation. In conclusion, our findings suggest that PDE5A downregulation or inhibition plays a causative role in exacerbating AAD likely by potentiating cGMP/PKG-mediated aortic SMC relaxation. Our findings highlight the need for caution in the clinical use of PDE5 inhibitors in patients at risk of aortic diseases. © 2025 The Pathological Society of Great Britain and Ireland.

血管平滑肌细胞磷酸二酯酶5失活加重主动脉瘤和夹层。
主动脉瘤及夹层(AAD)是一种死亡率很高的血管性疾病。先前的证据表明,使用磷酸二酯酶5A (PDE5A)抑制剂会增加AAD的风险。PDE5A是一种cgmp水解酶,在血管平滑肌细胞(SMCs)中富集,但SMCs特异性PDE5A在AAD发病机制中的作用尚不清楚。本研究通过单细胞RNA测序(scRNA-seq)、western blotting、免疫荧光和免疫组织化学染色分析PDE5A在人和小鼠主动脉组织中的表达。构建smc特异性PDE5A敲除(PDE5ASMC-/-)和PDE5A过表达(PDE5ASMC- oe)小鼠,并通过高脂肪饮食和血管紧张素II (Ang II)输注诱导AAD小鼠模型。通过体内成像和组织学分析来评估主动脉病变。PDE5A在人和小鼠AAD主动脉组织中表达降低,主要是在SMCs中。SMCs中PDE5A的药理抑制或基因敲除加剧了主动脉壁扩张和弹性蛋白纤维降解,增加了AAD的发病率。相比之下,PDE5ASMC-OE小鼠的AAD表型得到了恢复。在机制上,PDE5A表达影响肌球蛋白轻链(MLC)磷酸化,而MLC是SMC收缩性的关键调节因子。在PDE5ASMC-/-小鼠的AAD组织中,cgmp依赖性蛋白激酶(PKG)激活增加和MLC磷酸化降低表明主动脉舒张增强。总之,我们的研究结果表明,PDE5A下调或抑制可能通过增强cGMP/ pkg介导的主动脉SMC舒张而加重AAD。我们的研究结果强调了在有主动脉疾病风险的患者中临床使用PDE5抑制剂时需要谨慎。©2025英国和爱尔兰病理学会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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