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.