Matrix metalloproteinase-14 promotes LRP6 shedding in vascular smooth muscle cells and its expression is elevated in the tibial arteries from peripheral artery disease

Vascular smooth muscle cells (VSMCs) dedifferentiation is a key driver of peripheral artery disease (PAD), a common complication of atherosclerosis. Although matrix metallopeptidase 14 (MMP14) has been implicated in promoting VSMC dedifferentiation, the underlying mechanisms remain incompletely defined. Here, we demonstrate that MMP14 expression is markedly increased in PAD plaques, accompanied by elevated platelet-derived growth factor receptor-β (PDGFRβ) and reduced low-density lipoprotein receptor-related protein 6 (LRP6) levels, predominantly within VSMCs, compared with plaque-free arterial segments. Mechanistically, MMP14 selectively promoted LRP6 shedding without affecting LRP5 in VSMCs. Genetic or pharmacological inhibition of MMP14 increased LRP6 abundance, reduced PDGFRβ and SP1 expression, attenuated ERK phosphorylation, and suppressed VSMC proliferation and migration. In contrast, MMP14 overexpression produced opposite effects. Collectively, these findings indicate that MMP14 enhances VSMC proliferation and migration through modulation of the LRP6-PDGFRβ signaling axis.