Acute venous occlusion enhances matrix metalloprotease activity: Implications on endothelial dysfunction

Venous hypertension is associated with microvascular inflammation, restructuring, and apoptosis, but the cellular and molecular mechanisms underlying these events remain uncertain. In the present study, we tested the hypothesis that elevated venous pressure and reduction of shear stress induce elevated enzymatic activity. This activity in turn may affect endothelial surface receptors and promote their dysfunction. Using a rodent model for venous hypertension using acute venular occlusion, microzymographic techniques for enzyme detection, and immunohistochemistry for receptor labeling, we found increased activity of the matrix metalloproteases (MMPs) -1, -8, and -9 and tissue inhibitors of metalloproteases (TIMPs) -1 and -2 in both high- and low-pressure regions. In this short time frame, we also observed that elevated venule pressure led to two different fates for the vascular endothelial growth factor receptor-2 (VEGFR2); in higher-pressure upstream regions, some animals exhibited higher VEGFR2 expression, while others displayed lower levels upstream compared to their downstream counterparts with lower pressure. VEGFR2 expression was, on average, more pronounced upon application of MMP inhibitor, suggesting possible cleavage of the receptor by activated enzymes in this model. We conclude that venous pressure elevation increases enzymatic activity which may contribute to inflammation and endothelial dysfunction associated with this disease by influencing critical surface receptors. [Display omitted] ►Pressure elevation by acute venous occlusion enhances MMP-1, -8, and -9 activity in the rodent mesentery. ►MMP activity is inhibited in this model by application of broad-acting MMP inhibitor (GM6001). ►MMP activity appears to influence the expression of vascular endothelial growth factor receptor-2, with a trend for decreased receptor label density being observed upstream of the occlusion point. ►The presence of active MMPs during this acute experiment suggests a possible important role for MMPs in the early degenerative stages leading to chronic venous insufficiency.