Runx2-NLRP3 axis orchestrates matrix stiffness-evoked vascular smooth muscle cell inflammation

Arterial stiffening is a hallmark of chronic kidney disease (CKD)-related cardiovascular events and is primarily attributed to the elevated matrix stiffness. Stiffened arteries are accompanied by low-grade inflammation, but the causal effects of matrix stiffness on inflammation remain unknown. For analysis of the relationship between arterial stiffness and vascular inflammation, pulse-wave velocity (PWV) and aortic inflammatory markers were analyzed in an adenine-induced mouse model of CKD in chronological order. Compared with their control littermates, mice with CKD showed elevated arterial stiffness at the early stage of disease progression, which preceded the onset of vascular inflammation. Correspondingly, the increase of matrix stiffness induced vascular smooth muscle cells (VSMCs) to transdifferentiate into an inflammatory phenotype, as indicated by the increased expression and secretion of MCP-1, IL-6, IL-1β, and IL-18. RNA-sequencing analysis of stiff matrix-cultured VSMCs and bioinformatics analysis with the ChIP-Atlas database revealed the potential involvement of the transcription factor Runx2. The expression and the nuclear localization of Runx2 were significantly increased in stiff matrix-cultured VSMCs. High-throughput ChIP-sequencing and promoter luciferase assays further revealed that NLRP3 was directly transcriptionally regulated by Runx2. The inhibition of Runx2 or NLRP3 inflammasome abrogated the proinflammatory effect of matrix stiffening on VSMCs. Together, these data revealed that arterial stiffness precedes vascular inflammatory responses in CKD mice and that the Runx2-NLRP3 axis orchestrates matrix stiffness and the VSMC inflammatory phenotype, which may contribute to the pathogenic role in arterial stiffness-related vascular inflammation and CKD-related cardiovascular complications.NEW & NOTEWORTHY As a hallmark of chronic kidney disease (CKD), arterial stiffening is related to increased vascular inflammation and cardiovascular morbidity, whereas the underlying mechanism is unclear. The study demonstrates that increased arterial stiffness precedes the onset of vascular inflammation, and matrix stiffness stimulates the transdifferentiation of vascular smooth muscle cells (VSMCs) to an inflammatory phenotype via activating Runx2-NLRP3 signaling, which provides novel insights into CKD-related cardiovascular disorder treatment.