Key result
Inhibition or deletion of PARP1 suppressed the vascular smooth muscle cell phenotype switch in vivo and in vitro, indicating a pivotal role for PARP1 in determining VSMC plasticity.
Why the study?
Reversible differentiation of vascular smooth muscle cells is essential for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis.
Does PARP1 inhibition or deletion prevent VSMC phenotype switch and neointimal hyperplasia in arterial injury models?
Does PARP1 inhibition or deletion prevent VSMC phenotype switch and neointimal hyperplasia in arterial injury models?
PARP1 acts as a master regulator of VSMC plasticity, and its inhibition suppresses the synthetic proliferative phenotype, highlighting a potential therapeutic target for vascular pathologies like restenosis and atherosclerosis.
Smooth muscle cells are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Here we demonstrate the role of poly(ADP-ribose) polymerase 1 (PARP1) as a critical master regulator of vascular smooth muscle cells (VSMC) plasticity. A robust activation of PARP1 in VSMCs was observed in artery stenosis and atherosclerotic plaques of rodents and human. Inhibition or deletion of PARP1 suppressed the VSMC phenotype switch in vivo and in vitro. Further analysis identified myocardin and myocardin-associated serum response factor as substrates of PARP1-mediated poly(ADP-ribosyl)ation reaction. Poly(ADP-ribosyl)ation of myocardin and serum response factor dissociated the complex from CArG motif in the target promoter and then transcriptionally suppressed contractile protein expression. Moreover, we demonstrated that c-Jun mediated the stimulation of VSMC proliferation and migration by PARP1. Notably, interaction with myocardin is an important mechanism repressing c-Jun transcriptional activity in VSMCs. Poly(ADP-ribosyl)ation of myocardin and c-Jun disrupted myocardin-c-Jun interaction and abolished this repression to promote c-Jun transactivation and target gene expression, thus stimulating VSMC proliferation and migration. Our data reveal that activation of PARP1 not only suppresses contractile status but also promotes the synthetic proliferative phenotype of VSMCs, indicating a pivotal role for PARP1 in determining the phenotype of VSMCs. Targeting PARP1 may hold therapeutic potential for vascular pathologies.
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Xu et al. (2025) studied Arterial disease (atherosclerosis, restenosis). PARP1 inhibition or deletion vs. Wild-type or vehicle control was evaluated on Vascular smooth muscle cell phenotype switch (proliferation, migration, contractile protein expression). Inhibition or deletion of PARP1 suppressed the vascular smooth muscle cell phenotype switch in vivo and in vitro, indicating a pivotal role for PARP1 in determining VSMC plasticity.
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