Exercise-Induced Fxyd2 Upregulation Prevents VSMC Phenotypic Switching and Vascular Remodeling in Ang Ii-Induced Hypertension Through Parp1/Myocardin Axis

Objective: Hypertensive vascular remodeling is a critical pathological basis for target organ damage, with phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to synthetic phenotype serving as its core mechanism. Although aerobic exercise effectively mitigates hypertensive vascular remodeling, the molecular mechanisms by which it regulates VSMC phenotypic switching remain unclear. This study aims to reveal the vascular response molecules of aerobic exercise and explore whether FXYD2 mediates the effects of aerobic exercise on phenotypic transformation and vascular remodeling of hypertensive VSMC. Design and method: Hypertension was induced in C57BL/6 male mice by 6-week continuous Ang II infusion via osmotic minipumps (PBS as control). Hypertensive mice were randomly assigned to sedentary or moderate-intensity treadmill exercise groups. Blood pressure and vascular elasticity were measured using tail-cuff plethysmography and high-resolution ultrasound. Vascular remodeling was assessed by Sirius Red and Elastica Van Gieson staining. Aortic transcriptomes were analyzed by RNA sequencing to screen exercise-regulated genes. Functional validation utilized VSMC-specific Fxyd2 knockout mice and AAV9-mediated VSMC-specific FXYD2 overexpression. Downstream mechanisms were investigated using qPCR, Western blot, TurboID proximity labeling, Co-IP, and molecular docking. Results: Aerobic exercise significantly attenuated Ang II-induced blood pressure elevation, vascular stiffness, and remodeling. RNA-seq revealed marked aortic Fxyd2 downregulation in hypertensive mice, which was robustly reversed by exercise. Single-cell sequencing confirmed predominant Fxyd2 expression in VSMCs. In vitro, FXYD2 overexpression suppressed PDGF-BB-induced synthetic marker Col-I expression while enhancing contractile markers alpha-SMA and SM22alpha; Fxyd2 knockdown promoted synthetic switching. In vivo, VSMC-specific Fxyd2 knockout aggravated vascular wall thickening, further increased blood pressure, reduced contractile marker levels, and abolished exercise's protective effects in hypertensive mice. Conversely, AAV9-FXYD2 overexpression markedly alleviated remodeling. Mechanistically, FXYD2 directly interacted with PARP1 at Arg27, inhibiting PARP1-mediated ADP-ribosylation of Myocardin, thereby enhancing Myocardin-SRF complex binding to CArG-box elements and contractile gene transcription. Conclusions: FXYD2 downregulation exacerbates VSMC synthetic phenotypic switching and hypertensive vascular remodeling. Aerobic exercise upregulates FXYD2, which activates the PARP1/Myocardin axis to preserve contractile phenotype and ameliorate remodeling. As a novel endogenous PARP1 inhibitor, FXYD2 is central to exercise-mediated vascular protection in hypertension and represents a promising therapeutic target.