Exercise-induced FXYD2 upregulation prevents VSMC phenotypic switching and vascular remodeling in Ang II-induced hypertension through PARP1/myocardin axis
H Yu, X Zhou, G Hu, Z Li, N Feng, W GaoAbstract
Background
Hypertensive vascular remodeling is a critical determinant of target organ damage, driven by phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to synthetic phenotype. Although aerobic exercise effectively attenuates hypertensive vascular remodeling, the molecular mechanisms regulating VSMC phenotypic switching remain elusive.
Objectives
This study aims to identify vascular response molecules to aerobic exercise and determine whether FXYD2 mediates exercise-induced protection against VSMC phenotypic transformation and vascular remodeling in hypertension.
Methods
Hypertension was induced in C57BL/6 male mice via 6-week subcutaneous Ang II infusion (PBS as control). Mice were randomized to sedentary or moderate-intensity treadmill exercise groups. Blood pressure and vascular elasticity were assessed by tail-cuff plethysmography and high-resolution ultrasound. Vascular remodeling was evaluated by Sirius Red and Elastica Van Gieson staining. RNA sequencing of aortic samples identified exercise-regulated candidate molecules. VSMC-specific Fxyd2 knockout mice and AAV9-mediated VSMC-specific FXYD2 overexpression were used for functional validation. Downstream mechanisms were investigated using qPCR, Western blot, TurboID proximity labeling, Co-IP, and molecular docking.
Results
Aerobic exercise significantly attenuated blood pressure elevation, vascular stiffness, and remodeling in hypertensive mice. Transcriptomic analysis revealed that Fxyd2—predominantly expressed in VSMCs—was downregulated in hypertensive aorta and restored by exercise. In vitro, FXYD2 overexpression inhibited PDGF-BB-induced synthetic phenotype marker (Col-I) expression while upregulating contractile markers (α-SMA, SM22α); conversely, Fxyd2 knockdown promoted phenotypic switching. In vivo, VSMC-specific Fxyd2 knockout exacerbated vascular wall thickening, hypertension, and contractile marker loss, and abrogated exercise-mediated vascular protection. Conversely, AAV9-mediated FXYD2 overexpression ameliorated hypertensive vascular remodeling. Mechanistically, FXYD2 bound PARP1 via Arg27, inhibiting PARP1-mediated ADP-ribosylation of the transcriptional co-activator Myocardin. This enhanced Myocardin-SRF complex binding to CArG-box elements, promoting contractile phenotype marker expression.
Conclusions
FXYD2 downregulation aggravates VSMC phenotypic switching and vascular remodeling in hypertension. Exercise-induced FXYD2 upregulation activates the PARP1/Myocardin axis, preserving VSMC contractile phenotype and attenuating vascular remodeling. As a novel endogenous PARP1 inhibitor, FXYD2 represents a promising therapeutic target for hypertensive vascular disease.