Metalloproteinase 25 promotes abdominal aortic aneurysm and atherosclerosis

Matrix metalloproteinases (MMPs) mediate proinflammatory signaling, inflammatory cell recruitment, and extracellular matrix degradation. Involvement of MMPs in the disruption of vascular integrity is implicated in pathologies such as aneurysms and atherosclerosis. This study aimed to elucidate the role of MMP25 in the pathogenesis of abdominal aortic aneurysms (AAA) and atherosclerosis.

Wild-type (WT) and Mmp25^-/- mice underwent two AAA models: elastase-induced or pAAV/D377Y-mPCSK9 plus AngII infusion. Atherosclerosis was induced using the same adenovirus and a high fat diet for 12 or 20 weeks, generating early or advanced lesions in both genotypes.

MMP-25 was upregulated in both mouse and human AAA and atherosclerotic plaques. Mmp25^-/- mice showed reduced aortic expansion, lesional leukocytes, CD31⁺ microvessels, chemokine expression, MMP activity, disruption of the elastic layer and increased collagen content than those in WT mice, indicating reduced vascular remodeling in KO animals. Mechanistically, we demonstrate that MMP25 regulates NF-kB activation, TRAF6 and chemokine expression and MMP-9 activity in cultured macrophages and injured aortas. Mmp25-deficient macrophages also showed a diminished migratory capacity under proinflammatory conditions. In addition, Mmp25-deficient mice showed reduced atherosclerotic burden and lesion size in the aortic root compared to WT mice. Plaques from Mmp25^-/- mice were characterized by a more stable phenotype with lower lipid and inflammatory content and a smaller necrotic core compared to plaques from WT mice.

Our data suggest that MMP25 is involved in AAA and atherosclerosis progression. Thus, therapeutic interventions capable of reducing MMP25 expression may delay pathological vascular remodeling.