Vascular Smooth Muscle-Specific NLRP3 Hyperactivation Drives Arterial Intimal Hyperplasia in Mice.

Intimal hyperplasia is a major contributor to restenosis after vascular interventions and to atherosclerotic lesion progression, driven largely by vascular smooth muscle cell (VSMC) inflammatory activation, phenotypic switching, and maladaptive remodeling. While NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activity has been linked to vascular diseases, direct evidence that VSMC-intrinsic NLRP3 hyperactivation drives VSMC dysfunction and intimal hyperplasia in vivo has been lacking. Here, we generated a VSMC-specific Nlrp3 knock-in mouse (Nlrp3 (L351P/+/Myh11-Cre), "Nlrp3 (SMKI) ") and subjected it to carotid partial ligation under hypercholesterolemic conditions. VSMC Nlrp3 gain-of-function knock-in induced robust caspase-1 activation in vivo, including in unligated arteries, and markedly amplified injury-triggered inflammasome activation. Nlrp3 (SMKI) arteries exhibited heightened vascular inflammation (VCAM-1 upregulation and increased macrophage accumulation), enhanced activation of Gasdermin D (GSDMD) with increased cell death, and greater VSMC proliferative/migratory remodeling. These changes translated into significantly worsened neointimal lesion growth (increased intimal area and intima-to-media ratio). Interestingly, VSMC Nlrp3 gain-of-function accelerated vascular injury-induced lipid loading and VSMC-to-foam cell-like transition. Mechanistically, these pathological responses were accompanied by suppression of the transcription factor EB (TFEB) and broad impairment of lysosome-autophagy homeostasis, supporting TFEB-dependent lysosome-autophagy quality control as a central protective node that restrains not only lipid accumulation and foam cell transition, but also inflammatory activation, cell death, and proliferative/migratory remodeling during vascular injury. Collectively, these data provide the first direct evidence that VSMC NLRP3 hyperactivation drives VSMC dysfunction, intimal hyperplasia, and foam cell-like phenotypic switching, highlighting VSMC NLRP3-TFEB signaling as a highly translational therapeutic axis to limit restenosis and plaque progression.