Arterial origin-dependent susceptibility of vascular smooth muscle cells to prelamin A-induced senescence and rescue by umbilical artery-derived decellularized extracellular matrix.

OBJECTIVES: To determine whether prelamin A (PLA) induces distinct senescence responses in vascular smooth muscle cells (VSMCs) from different arterial origins and whether the extracellular matrix (ECM) modulates these effects. METHODS: PLA expression was examined in renal arteries from age-matched patients (59-63 years old). Human umbilical artery smooth muscle cells (huaSMCs) and human aortic smooth muscle cells (haoSMCs) were transduced with GFP- or PLA-expressing adenoviral vectors. Senescence, proliferation, DNA damage, apoptosis-related genes, ECM-related transcripts, and AKT/β-catenin signaling were assessed using X-GAL staining, Ki-67 staining, Cell Counting Kit-8 assays, γH2AX staining, quantitative PCR, and western blotting. HuaSMC-derived decellularized ECM (dECM) was applied to PLA-overexpressing haoSMCs. RESULTS: PLA expression differed significantly among renal arteries from age-matched patients (P < 0.005). PLA overexpression induced nuclear abnormalities, increased γH2AX and X-GAL staining, and reduced Ki-67 expression in both huaSMCs and haoSMCs (P < 0.001). However, downstream responses differed between the two cell types. PLA-overexpressing huaSMCs showed increased p53 without significant p21 induction and reduced BCL-2, BAX, and CASP3 expression, whereas overexpressing haoSMCs exhibited increased p53, p21, BCL2, and CASP3 expression (P < 0.05 or P < 0.001). COL3A1 expression decreased only in PLA-overexpressing haoSMCs. HuaSMC-derived dECM reduced senescence-associated staining, improved proliferation, increased p-AKT, and reduced β-catenin signaling in PLA-overexpressing haoSMCs. CONCLUSIONS: PLA induces senescence-associated abnormalities in VSMCs from different arterial origins, but the downstream signaling and ECM responses differ markedly. HuaSMC-derived dECM partially attenuates PLA-induced dysfunction in aortic VSMCs, potentially through modulation of AKT/β-catenin signaling.