Abstract 332: Deletion of ADAMTS7 in Mice Reveals a Role in Vascular Smooth Muscle Cell Response to Injury
The zinc metalloprotease ADAMTS7 was recently shown by GWAS to be a locus on chr15 for human coronary artery disease (CAD). However, the molecular mechanisms tying ADAMTS7 function to atherosclerosis are unknown. We hypothesized that ADAMTS7 may promote atherosclerosis by facilitating vascular smooth muscle cell (VSMC) proliferation and migration in vivo. We obtained mice containing an exon-trapping cassette between exon 4 and 5 of Adamts7, leading to premature termination of the mRNA and a grossly truncated protein. These mice bred normally and did not display any obvious phenotype. The exon trapping cassette also contained a LacZ reporter construct, allowing for XGal staining to determine gene expression. We assessed Adamts7 gene expression via XGal staining in multiple tissues of interest, including the heart, lungs, liver, and spleen. We also confirmed KO of the gene message through TaqMan rtPCR in additional tissues. We performed wire injury and sham surgeries of femoral arteries in adult Adamts7+/+ and -/- mice (N=4 and 5, respectively) and investigated lesion formation at 28 days. Adamts7-/- mice showed reduced neointima formation (64%), intima-to-media ratio (47%) and percent stenosis (61%) as compared to wild type. By immunohistochemistry and Trichrome staining we observed trends toward reduced VSMC proliferation (Ki67), reduced collagen IV and fibronectin matrix staining, and less disruption of laminin in ADAMTS7-/- injured arteries. Finally, ADAMTS7 immunofluorescence of human primary aortic SMCs revealed colocalization to cortactin domains at the leading edge of migrating SMCs as well as to cytoskeletal filaments. In summary, Adamts7 deletion attenuates the VSMC and matrix responses to arterial injury suggesting a role for ADAMTS7 in VSMC migration in atherosclerotic lesion initiation and progression.
- © 2012 by American Heart Association, Inc.