Adipocyte-Derived Serpina3c Protects Against High-Fat Diet-Related Arterial Remodeling by Inhibiting ADAMTS4 Activity

Obesity is closely associated with arterial stiffening and pathological vascular remodeling, yet its key molecular mechanisms remain incompletely understood. The endocrine function of adipocytes reveals the significance in regulating vascular diseases. This study investigated the adipocyte-derived serine protease inhibitor A3c (Serpina3c) in regulating vascular extracellular matrix (ECM) homeostasis and vascular smooth muscle cell (VSMC) phenotypic switching during obesity-related vascular injury. Serpina3c expression was significantly reduced in perivascular and epididymal adipose tissue in high-fat diet (HFD)-fed mice. Serpina3c deficiency exacerbated arterial stiffening and impaired vascular reactivity in HFD-fed mice, accompanied by ECM disorganization and VSMC switching toward a synthetic phenotype. Conversely, adipocyte-specific restoration of Serpina3c in perivascular/epididymal fat effectively reversed these abnormalities. Mechanistically, adipocyte-derived Serpina3c bound to the ADAMTS4 proteinase domain and inhibited its enzymatic activity, leading to decreased fibronectin cleavage. The reduction in fibronectin fragments suppressed integrin-mediated activation of the AKT1/NF-κB signaling pathway, ultimately maintaining ECM homeostasis and preventing the transition of VSMCs to a synthetic phenotype. Accordingly, the impaired vascular reactivity in HFD-fed Serpina3c knockout mice was rescued by an ADAMTS4 antagonist. Clinically, aneurysmal tissues from patients with a high body mass index showed decreased co‑localization of Kallistatin (the human homolog of Serpina3c) with ADAMTS4, alongside more severe aneurysmal progression and arterial structural damage. In summary, this study identifies the adipokine Serpina3c as a novel endogenous inhibitor of ADAMTS4 that limits ECM proteolysis and VSMC synthetic switching by attenuating fragmented fibronectin-mediated AKT1/NF-κB signaling. Targeting Serpina3c provides a new therapeutic approach for obesity-related arterial remodeling.