Abstract 5494: ADAMTS-7 is Critical for Vascular Smooth Muscle Cell Migration and Neointima Formation in Injured Rat Carotid Artery

Abstract

Migration of vascular smooth muscle cells (VSMCs) plays an essential role during vascular development, in response to vascular injury and during atherogenesis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases during VSMCs migration. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), a recently described family of proteinases, is capable of degrading vascular ECM proteins. However, the relevance of ADAMTS family members in cardiovascular disease is poorly understood. In this study, we sought to determine whether ADAMTS-7 is involved in VSMC migration and neointima formation in response to vascular injury. Denudation of rat carotid arteries with a balloon catheter led to an initial decrease of ADAMTS-7 protein level in injured compared with sham-operated arteries within the first 24 hours, followed by a subsequent increase during the 4 to 14 days after injury. In primary VSMCs, the pro-inflammatory cytokine TNF-α increased ADAMTS-7 mRNA level through transcriptional factors nuclear factor-kappa B and AP-1. VSMCs infected with ADAMTS-7 adenovirus (Ad-ADAMTS-7) greatly accelerated their migration and invasion in vitro . Conversely, suppression of ADAMTS-7 expression by small interfering RNA (siRNA) markedly retarded VSMC movement by 50% than that with scramble siRNA. At 7 days after injury, the neointimal area of the vascular wall was sixfold greater in Ad-ADAMTS-7-infected than that in Ad-GFP-infected vessels (3.10±0.88 vs. 0.52±0.28 ×10 4 μm 2 , n=8 per group, P <0.05). By contrast, perivascular administration of ADAMTS-7 siRNA, but not scramble siRNA to injured arteries resulted in prolonged ADAMTS-7 silencing and diminished neointimal thickening without affecting medial areas. This inhibitory effect was sustained up to 14 days after injury. As well, ADAMTS-7 mediated degradation of the vascular ECM cartilage oligomeric matrix protein (COMP) in injured vessels, which might facilitate VSMC migration and neointimal thickening. ADAMTS-7 directs VSMC migration and neointima formation and therefore may serve as a novel therapeutic target for vascular restenosis and atherogenesis.