Contribution of NLRP3-GSDMD axis to PDGF-BB-induced vascular smooth muscle cell phenotypic transition.

Intimal hyperplasia, a pathological form of vascular remodeling, is a hallmark of several cardiovascular diseases, including restenosis following angioplasty. Vascular smooth muscle cell (VSMC) phenotypic transition plays a critical role in the development of vascular intimal hyperplasia. This study investigates the role of the NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and its downstream effector, gasdermin D (GSDMD), in regulating VSMC phenotypic transition and their implications in the development of intimal hyperplasia. In primary cultured VSMCs, platelet-derived growth factor BB (PDGF-BB) stimulated activation of the NLRP3-GSDMD axis, promoting inflammation, proliferation, and migration. Pharmacological inhibition of the inflammasome with the caspase-1 inhibitor YVAD significantly attenuated PDGF-BB-induced GSDMD activation and lactate dehydrogenase release. Furthermore, silencing the gene effectively blocked PDGF-BB-induced VSMC proliferation, migration, and inflammatory responses. In vivo, intimal hyperplasia was modeled by performing carotid artery ligation in hypercholesterolemic mice. In mice, vascular injury led to increased inflammasome and GSDMD activation, enhanced pyroptosis, elevated vascular inflammation, macrophage infiltration, and a shift to a synthetic VSMC phenotype, primarily within the VSMC-rich intimal region. In contrast, these pathological changes were significantly attenuated in mice. These findings provide novel insights into the critical role of the NLRP3-GSDMD axis in VSMC phenotypic transition and vascular injury-induced intimal hyperplasia, suggesting that targeting this pathway may offer a promising therapeutic strategy for cardiovascular diseases characterized by intimal hyperplasia. This study reveals that the NLRP3-GSDMD axis drives PDGF-BB-induced dedifferentiation transition and inflammation of vascular smooth muscle cells (VSMCs), contributing to intimal hyperplasia. These findings identify NLRP3-GSDMD signaling as a novel driver of pathological vascular remodeling and a potential therapeutic target for intimal hyperplasia-associated cardiovascular diseases.