Abstract 15589: Matrix Metalloproteinase-12 Controls Arterial Stiffness in Vascular Remodeling
Background--- Increased arterial stiffening is a hallmark of aging and a common consequence of vascular remodeling. The mechanisms mediating changes in vascular stiffness remain poorly understood. We have combined vascular injury, genome-wide profiling, and mouse modeling to identify the molecular mechanism(s) responsible for arterial stiffening during vascular remodeling.
Methods and Results_Vascular remodeling induced by fine-wire femoral artery injury was investigated in SMA-GFP mice. In this transgenic line, the SMα-actin promoter drives GFP expression, so VSMC dedifferentiation at sites of injury can be visualized the by loss of GFP fluorescence. Analysis of these injury sites by atomic force microscopy (AFM) revealed increased stiffening coincident with vascular remodeling. We then microdissected the GFP-negative (stiff areas) and GFP positive (soft areas) of injured and uninjured arteries, respectively, and performed an Affymetrix-based microarray analysis to identify stiffness-regulated genes. The microarray data showed dramatically high induction of MMP-12 mRNA (∼17-fold) in injury sites as compared to uninjured controls. The induction of MMP-12 mRNA greatly exceeded that of any other MMP in the genome. RT-qPCR and immunostaining confirmed induction of MMP12 mRNA and protein at sites of injury. Next, we compared arterial stiffness after arterial injury in wild-type and MMP-12 KO mice. AFM showed that arterial stiffening 14 days after injury was largely eliminated in MMP12 KO mice (Injured / uninjured control : 1.04 fold) vs. WT (Injured / uninjured control : 4.88 fold). Experiments to date indicate that the ratio of neointimal to medial areas is also decreased in the MMP-12 KO mice (0.47±0.15% p < 0.05; n=3) as compared to WT mice (1.53±0.28%; n=5). Immunostaining of injury sections demonstrates that MMP-12 expression is dramatically increased in dedifferentiated VSMCs. We are currently determining the relative contributions of macrophage and VSMC MMP-12 to arterial stiffness and the effect of MMP-12 elastinolytic activity on vessel biomechanics.
Conclusion--- MMP-12 is a critical regulator of arterial stiffening during vascular remodeling, and that this effect is associated with reduced neointima formation.
- © 2012 by American Heart Association, Inc.