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

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 (PDE5A SMC−/− ) and PDE5A‐overexpressing (PDE5A SMC‐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 PDE5A SMC‐OE mice. Mechanistically, PDE5A expression influenced myosin light chain (MLC) phosphorylation, a key regulator of SMC contractility. In AAD tissues from PDE5A SMC−/− 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.