TNFα-induced Expression of Adamts7 Affects Primary Mouse Smooth Muscle Cell Migration Ex Vivo

ADAMTS7 has recently been identified as a novel genomic locus associated with coronary artery disease (CAD) in humans. We have recently shown that deficiency of Adamts7 in hyperlipidemic mouse models reduces atherosclerosis following prolonged western diet feeding, however the mechanism of this reduction remains unknown. Using a β-galactosidase (β-gal) reporter, we observed that vascular Adamts7 expression is induced in response to both mechanical injury and western diet feeding in a transient manner, and this expression predominantly colocalizes to vascular smooth muscle cells (VSMCs). We investigated the ability of multiple cytokines and growth factors (PDGF-BB, TNFα, IFNγ, and Angiotensin II) to stimulate Adamts7 expression in primary mouse VSMCs, and found that of these only TNFα induced Adamts7 expression (5.5-fold, p=0.0007). We determined the expression of Adamts7 and TNFα in whole aortas and aortic roots of Apoe-/- mice at various timepoints of western diet feeding, and found trends towards increased Adamts7 expression while TNFα expression consistently increased over the course of the experiment (4.4-fold increase, p=0.002). We next examined proliferation and migration of primary VSMCs from Adamts7 WT and KO animals. Unstimulated Adamts7 KO VSMCs had no observable difference in migration as compared to WT controls. However, in the setting of TNFα stimulation we observed a decrease in migration of Adamts7 KO VSMCs plated on collagen I (50% reduction, p=0.02) and laminin (60% reduction, p=0.0002). Finally, using both public and private data sets, we assessed if associations exist between SNPs in and around the human ADAMTS7 locus and the expression of ADAMTS7 in relevant tissues. In small data sets we find that SNPs with genome-wide association with CAD also associate with ADAMTS7 expression, and the direction of this association is consistent with our in vivo reduction of atherosclerosis in Adamts7 KO animals. In summary, Adamts7 expression in mice is induced in response to vascular injury, perhaps mediated by TNFα expression, and this induction can modulate VSMC migration. These observations present a novel mechanistic paradigm for ADAMTS7 modulation of atherogenesis and suggest its inhibition might reduce CHD in clinic.