Early Differential MMP-2 and -9 Dynamics During Flow-Induced Arterial and Vein Graft Adaptations

Background: Arteries and vein grafts respond differently to reductions in flow, with arteries demonstrating inward remodeling through only limited structural reorganization of the media and vein grafts developing a thickened intima, with little change in the external diameter. In an effort to mechanistically explore the biology of this contrasting behavior, we hypothesized that this differential response in flow-mediated remodeling is driven by unique temporal expression patterns and functional activities of the matrix metalloproteinase (MMP)-2 and -9, key effectors of blood vessel architecture remodeling. Material and methods: In rabbits, bilateral carotid vein grafting was coupled with unilateral partial distal ligation to create a sevenfold flow differential between sides. Vein grafts and proximal carotid arteries were then harvested for morphological and biochemical studies at time points ranging from 1 to 14 days. Results: Vein grafts demonstrated an early, transient increase in pro-MMP-9 within adherent monocytes and endothelial cells. This was followed by a delayed increase in smooth muscle cell active MMP-2, which was coincident with the onset of intimal thickening at days 7 and 14 and significantly elevated by low flow. In contrast, arteries showed no elevation in pro MMP-9 above baseline, but demonstrated a transient increase in latent MMP-2 preceding the flow-mediated change in vessel diameter. Conclusions: These data provide evidence for unique and independent roles of MMP-2 and -9 in the process of hemodynamically driven vascular remodeling. [Copyright &y& Elsevier]