# Vascular Smooth Muscle–Specific NLRP3 Hyperactivation Drives Arterial Intimal Hyperplasia in Mice

## TL;DR

Hyperactivation of the NLRP3 inflammasome in vascular smooth muscle cells worsens arterial thickening and inflammation in mice, suggesting a new therapeutic target for vascular diseases.

## Contribution

First direct evidence that VSMC-specific NLRP3 hyperactivation drives intimal hyperplasia and foam cell-like transition in vivo.

## Key findings

- VSMC NLRP3 gain-of-function increases vascular inflammation and cell death.
- NLRP3 hyperactivation worsens neointimal lesion growth and lipid accumulation.
- Impaired TFEB-dependent lysosome-autophagy homeostasis contributes to VSMC dysfunction.

## Abstract

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, “Nlrp3SMKI”) 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. Nlrp3SMKI 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.