Chronic sympathetic activation decreases atherosclerotic inflammation by regulating β3AR/p-CREB/SFRP5 in perivascular adipose tissue

Background Residual cardiovascular risk remains high despite optimal medical therapy. Perivascular adipose tissue (PVAT) acts as a critical transducer of “outside-in” signaling in atherosclerosis. While chronic sympathetic nervous system (SNS) activation is known to promote vascular inflammation, the specific mechanism by which SNS dysregulation affects PVAT phenotype and subsequent plaque stability remains elusive. Purpose We aimed to investigate the relationship between chronic sympathetic activation, PVAT inflammation, and plaque vulnerability, and to delineate the molecular mechanism involving the β3-adrenergic receptor (Adrb3)/Sfrp5 axis. Methods Clinical Cohort: We conducted a retrospective study including patients with serum norepinephrine (NE) levels. PVAT inflammation was quantified using the CT-derived Fat Attenuation Index (FAI). Plaque characteristics and Major Adverse Cardiovascular Events (MACE) were analyzed. Pre-clinical Models: ApoE-/- mice were fed a high-fat diet (HFD) for up to 20 weeks to induce atherosclerosis and chronic sympathetic activation. PVAT-specific overexpression of Adrb3 was achieved using an adeno-associated virus (AAV-UCP1-OE Adrb3) to evaluate its therapeutic potential. Results 1. Clinical Observations: In the clinical cohort, markers of high sympathetic tone (higher serum NE) were significantly correlated with increased PVAT inflammation and a greater burden of high-risk plaques (HRP). Kaplan-Meier analysis showed that patients with high sympathetic tone and high FAI had the lowest event-free survival. 2. Animal Mechanism: In HFD-fed mice, chronic sympathetic activation was accompanied by significant PVAT inflammation and downregulation of Adrb3 expression. 3. Therapeutic Intervention: PVAT-specific overexpression of Adrb3 significantly attenuated atherosclerotic plaque progression and reduced macrophage infiltration (CD68+). Mechanistically, restoration of Adrb3 signaling promoted the secretion of Secreted Frizzled-Related Protein 5 (Sfrp5), an anti-inflammatory adipokine, via the p-CREB pathway, thereby mitigating vascular inflammation. Conclusion Chronic sympathetic activation is a potent driver of PVAT inflammation and plaque instability, independent of traditional risk factors. We identified the downregulation of the Adrb3/p-CREB/Sfrp5 axis in PVAT as a key maladaptive mechanism linking neural dysregulation to vascular disease. Targeting this neuro-adipose axis represents a novel therapeutic strategy to reduce residual cardiovascular risk.