Author(s): SHI, L., ZHANG, Y., Institution: BEIJING SPORT UNIVERSITY, Country: CHINA, Abstract-ID: 284

INTRODUCTION:
Resistance artery remodeling in hypertension involves vascular smooth muscle cell (VSMC) dysfunction and ion channel impairment. Whether aerobic exercise restores KV2.1 channel function through AKAP150-mediated signaling remains unclear. We investigated the role of the AKAP150/CaN/NFATc3 axis in exercise-induced vascular improvement.
METHODS:
Spontaneously hypertensive rats (SHR) and smooth muscle-specific AKAP150 knock-in (smKI) mice underwent 12-week moderate-intensity treadmill training. Systolic blood pressure (SBP) was monitored via tail-cuff plethysmography. Mesenteric and cerebral artery reactivity was assessed by wire myography. KV2.1 currents were recorded using whole-cell patch-clamp. Protein and mRNA expression of AKAP150, CaN, NFATc3, KV2.1, and VSMC phenotypic markers (α-SM-actin, calponin, OPN) were analyzed by Western blot and RT-qPCR.
RESULTS:
1. Exercise lowered SBP in SHR (~17 mmHg, P<0.05) and AKAP150 smKI mice (~14 mmHg, P<0.05).
2. KV2.1 current density was reduced in SHR VSMCs (−12.5±1.2 vs. WKY −18.3±1.5 pA/pF) and restored by exercise (−16.8±1.3 pA/pF, P<0.05). KV2.1 protein expression followed a similar pattern.
3. AKAP150 membrane localization increased in hypertension (~22%, P<0.05) and was reduced by exercise. Phospho-NFATc3 (inactive) decreased in SHR (0.32±0.04 vs. WKY 0.85±0.06) and was normalized post-exercise (0.71±0.05, P<0.05).
4. AKAP150 smKI mice exhibited similar KV2.1 suppression and increased medial thickness, both reversed by exercise.
5. Dedifferentiation marker OPN mRNA increased ~3.2-fold in SHR (P<0.05) and was reduced by exercise, while contractile markers (α-SM-actin, calponin) showed converse regulation.


CONCLUSION:
Our findings demonstrate that aerobic exercise ameliorates hypertensive vascular remodeling by suppressing AKAP150/CaN/NFATc3 signaling in VSMCs. This pathway underlies both the downregulation of KV2.1 channels—a key determinant of membrane potential and vasoconstriction—and the shift toward a synthetic, pro-remodeling VSMC phenotype. The recapitulation of these defects in AKAP150 smKI mice and their rescue by exercise confirm AKAP150 as a central orchestrator of channelopathy and phenotypic switching in hypertension. These results provide a mechanistic basis for exercise as a non-pharmacological strategy to improve vascular function and structure, highlighting AKAP150 as a potential target for therapeutic intervention in hypertensive vasculopathy.