Matrix metalloproteinase-12 in arterial diseases: context-dependent mechanisms of vascular remodeling and therapeutic implications

Figures

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  Figure 1. Upstream signaling pathways that regulate MMP12 transcription in vascular remodeling. Th2 cytokines (IL-4/IL-13) activate JAK–STAT6 signaling to induce MMP12 expression, whereas IFN-γ counter-regulates this program. GM-CSF enhances AP-1 activity through Ras–PI3K–Akt signaling. Innate immune and chemokine cues, including TLR4–TRIF and CXCL12 (SDF-1)–CXCR4, promote NF-κB signaling that cooperates with AP-1 to drive MMP12 transcription. TGF-β signaling and nuclear receptors PPARα/γ restrain MMP12 expression, while H3K9me2-mediated chromatin repression limits transcription factor access to the MMP12 promoter. Created with BioRender.com.

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  Figure 2. EDPs link MMP-12–driven elastolysis to self-amplifying vascular remodeling. MMP-12 degrades elastin and tropoelastin, releasing bioactive EDPs. Acting as matrikines, EDPs and sustained MMP-12 activity together establish a feed-forward pathogenic program in vascular disease. This circuitry expands proteolysis by engaging MMP activation cascades, promotes monocyte/macrophage recruitment and pro-inflammatory polarization, and is associated with vasa vasorum angiogenesis, LDL oxidation and VSMC phenotypic switching and arterial calcification, thereby accelerating maladaptive vascular remodeling. Created with BioRender.com.