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

Area of Science:

• Cardiovascular Biology
• Vascular Medicine
• Molecular Cardiology

Background:

• Aortic dissection (AD) is a critical condition involving vascular smooth muscle cell (VSMC) phenotypic switching.
• The role of exercise in AD pathogenesis and its underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate if exercise attenuates AD by modulating VSMC phenotype.
• To elucidate the molecular mechanisms, specifically the RUNX1-PDE5A axis, involved in exercise's effects on AD.

Main Methods:

• Analysis of human aortic tissues for VSMC markers and PDE5A expression.
• Establishment of a mouse model of AD with and without exercise intervention.
• Utilizing RNA sequencing, gain/loss-of-function experiments, and mechanistic assays to study RUNX1 and PDE5A.

Main Results:

• Exercise improved survival and reduced AD incidence in mice, preserving contractile VSMC phenotype.
• PDE5A expression was reduced in AD tissues but upregulated by exercise; its overexpression attenuated AD.
• RUNX1 was identified as a repressor of PDE5A, suppressed by exercise, and its inhibition preserved VSMC contractility and reduced AD.

Conclusions:

• A novel RUNX1-PDE5A axis mediates exercise's beneficial effects against AD.
• Exercise attenuates AD by suppressing RUNX1-mediated repression of PDE5A, maintaining VSMC contractile phenotype.
• The RUNX1-PDE5A pathway presents a potential preventive target for AD.