Recent histologic and immunocytochemical evidence of venous leg ulcers supports the hypothesis that lesions observed at different stages of chronic venous insufficiency may be associated with, and possibly caused by, an inflammatory process. Evidence has been obtained that venous valve deficiency may be associated with leukocyte infiltration into valve leaflets; therefore, it is hypothesized that an essential event in the inflammatory cascade is the enzymatic degradation of the valve leaflets and venous wall. The metalloproteinases (MMP) in veins exposed to elevated pressures up to 6 weeks were examined in a rat femoral fistula model with venous hypertension. Zymography shows increased activity of pro-MMP-2 at 3 and 6 weeks. MMP-2 and MMP-9 activity was predominantly observed at days 7 and 21 after creation of the fistula. The degree of extracellular matrix remodeling correlates with the morphological finding of macroscopic lesions. Therefore, the MMP-2 and MMP-9 activation is already present in veins days after exposure to elevated blood pressure and coincides with periods of early alterations in the valve morphology and early forms of reflux.