Key result
Adipocyte-derived Serpina3c reverses diet-induced arterial stiffening by inhibiting ADAMTS4-mediated fibronectin cleavage in mice.
Why the study?
The key molecular mechanisms linking obesity to arterial stiffening and pathological vascular remodeling remain incompletely understood, prompting investigation into the role of adipocyte-derived Serpina3c in vascular extracellular matrix homeostasis and vascular smooth muscle cell phenotypic switching.
Does adipocyte-derived Serpina3c prevent high-fat diet-related arterial stiffening, extracellular matrix proteolysis, and vascular smooth muscle cell phenotypic switching in mice by inhibiting ADAMTS4 activity?
Does adipocyte-derived Serpina3c prevent high-fat diet-related arterial stiffening, extracellular matrix proteolysis, and vascular smooth muscle cell phenotypic switching in mice by inhibiting ADAMTS4 activity?
This preclinical study identifies adipocyte-derived Serpina3c as a novel endogenous ADAMTS4 inhibitor that protects against obesity-related arterial stiffening and pathological vascular remodeling by suppressing fragmented fibronectin-mediated AKT1/NF-κB signaling.
Answers are grounded in this paper and cite their sources.
Serpina3c-ADAMTS4 modulation merits human mechanistic studies; leaves open whether restoration mitigates arterial stiffening in obese patients.
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.
No takes yet. Share an insight, caveat, or question.
Wu et al. (2026) studied High-fat diet-related arterial remodeling and obesity-related vascular injury. Adipocyte-specific Serpina3c restoration / recombinant Serpina3c / ADAMTS4 antagonist vs. Serpina3c knockout (3cKO) / wild-type control was evaluated on Arterial stiffening (pulse wave velocity), vascular reactivity, ECM disorganization, and VSMC phenotypic switching. Adipocyte-derived Serpina3c binds to and inhibits ADAMTS4 activity to reduce fibronectin cleavage and AKT1/NF-κB signaling, reversing high-fat diet-induced arterial stiffening in mice.
Synapse has enriched 10 related papers. Consider them for comparative context: