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

Maladaptive vascular remodeling is a shared feature of diverse arterial disorders and arises from a self-reinforcing interplay between inflammation and extracellular matrix (ECM) turnover. Matrix metalloproteinase-12 (MMP-12), also known as macrophage elastase, has emerged as a context-dependent mediator within this crosstalk. This review synthesizes current knowledge on the structure, function, and regulation of MMP-12, detailing its multifaceted roles across arterial diseases. Divergent observations across experimental models and clinical settings can be better understood when MMP-12 activity is interpreted in relation to the inflammatory milieu, temporal disease stage, and substrate landscape. Within this framework, MMP-12 can act as a matrix-degrading protease, an amplifier of inflammatory cell recruitment, a regulator of protease cascades, or, in selected settings, a homeostatic modulator of inflammatory resolution. Finally, we discuss the opportunities and translational challenges of MMP-12-targeted strategies, emphasizing that therapeutic interpretation should be constrained by disease context, evidence level, and model heterogeneity.