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

Area of Science:

• Cardiovascular Biology
• Inflammation Research
• Vascular Cell Biology

Background:

• Intimal hyperplasia contributes to restenosis and atherosclerosis, driven by vascular smooth muscle cell (VSMC) dysfunction.
• NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation is implicated in vascular diseases, but its role in VSMC-intrinsic pathology was unclear.

Purpose of the Study:

• To investigate the direct impact of VSMC-intrinsic NLRP3 inflammasome hyperactivation on vascular injury responses and intimal hyperplasia in vivo.
• To elucidate the molecular mechanisms linking VSMC NLRP3 activation to pathological remodeling and foam cell formation.

Main Methods:

• Generated a VSMC-specific NLRP3 gain-of-function knock-in mouse model (Nlrp3 SMKI).
• Subjected Nlrp3 SMKI mice to carotid artery partial ligation under hypercholesterolemic conditions.
• Analyzed vascular inflammation, cell death, proliferation, lipid loading, and autophagy-lysosome homeostasis.

Main Results:

• VSMC NLRP3 gain-of-function induced caspase-1 activation and amplified inflammasome responses in arteries.
• Nlrp3 SMKI arteries showed increased vascular inflammation, Gasdermin D activation, cell death, and VSMC proliferation/migration.
• Hyperactivation led to worsened neointimal lesion growth, accelerated lipid loading, and VSMC-to-foam cell transition via TFEB suppression and impaired autophagy.

Conclusions:

• VSMC-intrinsic NLRP3 hyperactivation directly drives VSMC dysfunction, intimal hyperplasia, and foam cell-like switching.
• The NLRP3-TFEB signaling axis is a critical regulator of vascular injury responses, controlling inflammation, cell death, and lipid metabolism.
• Targeting VSMC NLRP3-TFEB pathway represents a potential therapeutic strategy for restenosis and atherosclerotic plaque progression.