Exercise Attenuates Aortic Dissection Via PDE5A-Mediated Inhibition of Vascular Smooth Muscle Cell Phenotypic Switch

Aortic dissection (AD) is a life-threatening condition and involves pathological vascular smooth muscle cell (VSMC) phenotypic switching from a contractile to a synthetic state. Although exercise confers broad cardiovascular benefits, its role in AD pathogenesis remains unclear. This study aimed to determine whether exercise attenuates AD by modulating VSMC phenotype and to elucidate the underlying molecular mechanism.

Human aortic tissues from AD patients were analyzed for VSMC phenotypic markers and PDE5A (phosphodiesterase 5A) expression. A β-aminopropionitrile induced AD model was established in wild-type mice with or without treadmill exercise intervention. RNA sequencing, gain- and loss-of-function experiments, and mechanistic assays were employed to investigate the roles of PDE5A and its transcriptional regulator RUNX1 (runt-related transcription factor 1).

In human AD lesional tissues, contractile VSMC markers (MYH11 [myosin heavy chain 11], CNN1 [calponin 1], and α-SMA [alpha-smooth muscle actin]) were significantly downregulated, whereas the synthetic marker osteopontin was upregulated. In β-aminopropionitrile-induced AD mice, exercise improved survival, reduced aortic dilation and AD incidence, and preserved the contractile VSMC phenotype. RNA-seq analysis identified PDE5A as a key exercise-responsive gene. PDE5A expression was reduced in human AD lesional tissues and β-aminopropionitrile-treated mice but was upregulated by exercise. VSMC-specific overexpression of PDE5A attenuated AD progression, whereas PDE5A inhibition abolished the attenuating effects of exercise. We further identified RUNX1 as a transcriptional repressor of PDE5A that is upregulated in AD conditions and suppressed by exercise. Inhibition of RUNX1 upregulated PDE5A expression, preserved VSMC contractility, and reduced AD incidence.

In conclusion, we identify a novel RUNX1-PDE5A axis that mediates the beneficial effects of exercise against AD. Exercise attenuates AD by reducing RUNX1-mediated transcriptional repression of PDE5A, thereby maintaining VSMC contractile phenotype. These findings highlight the RUNX1-PDE5A pathway as a promising preventive target.