Decreased PGE(2) Content Reduces MMP-1 Activity and Consequently Increases Collagen Density in Human Varicose Vein

Varicose veins are elongated and dilated saphenous veins. Despite the high prevalence of this disease, its pathogenesis remains unclear. AIMS: In this study, we investigated the control of matrix metalloproteinases (MMPs) expression by prostaglandin (PG)E(2) during the vascular wall remodeling of human varicose veins. METHODS AND RESULTS: Varicose (small (SDv) and large diameter (LDv)) and healthy saphenous veins (SV) were obtained after surgery. Microsomal and cytosolic PGE-synthases (mPGES and cPGES) protein and mRNA responsible for PGE(2) metabolism were analyzed in all veins. cPGES protein was absent while its mRNA was weakly expressed. mPGES-2 expression was similar in the different saphenous veins. mPGES-1 mRNA and protein were detected in healthy veins and a significant decrease was found in LDv. Additionally, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), responsible for PGE(2) degradation, was over-expressed in varicose veins. These variations in mPGES-1 and 15-PGDH density account for the decreased PGE(2) level observed in varicose veins. Furthermore, a significant decrease in PGE(2) receptor (EP4) levels was also found in SDv and LDv. Active MMP-1 and total MMP-2 concentrations were significantly decreased in varicose veins while the tissue inhibitors of metalloproteinases (TIMP -1 and -2), were significantly increased, probably explaining the increased collagen content found in LDv. Finally, the MMP/TIMP ratio is restored by exogenous PGE(2) in varicose veins and reduced in presence of an EP4 receptor antagonist in healthy veins. CONCLUSIONS: In conclusion, PGE(2) could be responsible for the vascular wall thickening in human varicose veins. This mechanism could be protective, strengthening the vascular wall in order to counteract venous stasis.