Early effects of arterial hemodynamic conditions on human saphenous veins perfused ex vivo

Exposure to the arterial hemodynamic environment is thought to be a potenti al trigger for the pathological remodeling of saphenous vein grafts. Using matched pairs of freshly isolated human saphenous vein, we analyzed the ear ly effects of ex vivo hemodynamic conditions mimicking the venous (native) compared with arterial (graft) environment on the key components of vascula r remodeling, ie, matrix metalloproteinase (MMP)-9 and MMP-2 and cell proli feration. Interestingly, we found that arterial conditions halved latent MM P-9 (50+/-11%, P=0.01) and MMP-2 (44+/-6%, P=0.005) levels relative to matc hed vein pairs maintained ex vivo under venous perfusion for up to 3 days. Immunostaining supported decreased MMP levels in the innermost area of arte rially perfused veins. Either decreased synthesis or increased posttranslat ional processing may decrease MMP zymogen levels. Biosynthetic radiolabelin g showed that arterial perfusion actually increased MMP-9 and MMP-2 product ion. When we then examined potential pathways for MMP zymogen processing, w e found that arterial conditions did not affect the expression of MT-MMP-1, a cell-associated MMP activator, but that they significantly increased the levels of superoxide, another MMP activator, suggesting redox-dependent MM P processing. Additional experiments indicated that increased superoxide un der arterial conditions was due to diminished scavenging by decreased extra cellular superoxide dismutase. Arterial perfusion also stimulated cell prol iferation (by 220% to 750%) in the majority of vein segments investigated. Our observations support the hypothesis that arterial hemodynamic condition s stimulate early vein graft remodeling. Furthermore, physiological arteria l flow may work to prevent pathological remodeling, particularly the format ion of intimal hyperplasia, through rapid inactivation of secreted MMPs and , possibly, through preferential stimulation of cell proliferation in the o uter layers of the vein wall.