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Previous evidence has suggested an elevated risk of AAD associated with the use of phosphodiesterase 5A (PDE5A) inhibitors. PDE5A, a cGMP\u2010hydrolyzing enzyme, is enriched in vascular smooth muscle cells (SMCs), but the role of SMC\u2010specific PDE5A in the pathogenesis of AAD is still unclear. In this study, PDE5A expression in human and mouse aortic tissues was analyzed by single\u2010cell RNA sequencing (scRNA\u2010seq), western blotting, immunofluorescence, and immunohistochemistry staining. SMC\u2010specific PDE5A knockout (PDE5A<jats:sup>SMC\u2212\/\u2212<\/jats:sup>) and PDE5A\u2010overexpressing (PDE5A<jats:sup>SMC\u2010OE<\/jats:sup>) mice were constructed and utilized, along with an AAD mouse model induced by a high\u2010fat diet and angiotensin II (Ang II) infusion. <jats:italic>In vivo<\/jats:italic> 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 PDE5A<jats:sup>SMC\u2010OE<\/jats:sup> mice. Mechanistically, PDE5A expression influenced myosin light chain (MLC) phosphorylation, a key regulator of SMC contractility. In AAD tissues from PDE5A<jats:sup>SMC\u2212\/\u2212<\/jats:sup> mice, increased cGMP\u2010dependent 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\u2010mediated aortic SMC relaxation. Our findings highlight the need for caution in the clinical use of PDE5 inhibitors in patients at risk of aortic diseases. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6411","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T01:35:33Z","timestamp":1743298533000},"page":"144-159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phosphodiesterase 5 inactivation in vascular smooth muscle cells aggravates aortic aneurysm and dissection"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-4478","authenticated-orcid":false,"given":"Yuyao","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College  Beijing PR China"},{"name":"Department of Vascular Surgery, Peking 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