Decreased PGE2 Content Reduces MMP-1 Activity and Consequently Increases Collagen Density in Human Varicose Vein

Ingrid Gomez,Liliane Louedec,Guy Leséche,Chabha Benyahia,Marie-Paule Jacob,Dan Longrois,Xavier Norel,Utpal Sen

doi:10.1371/journal.pone.0088021

Abstract

Varicose veins are elongated and dilated saphenous veins. Despite the high prevalence of this disease, its pathogenesis remains unclear.AimsIn this study, we investigated the control of matrix metalloproteinases (MMPs) expression by prostaglandin (PG)E2 during the vascular wall remodeling of human varicose veins.Methods and ResultsVaricose (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 PGE2 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 PGE2 degradation, was over-expressed in varicose veins. These variations in mPGES-1 and 15-PGDH density account for the decreased PGE2 level observed in varicose veins. Furthermore, a significant decrease in PGE2 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 PGE2 in varicose veins and reduced in presence of an EP4 receptor antagonist in healthy veins.ConclusionsIn conclusion, PGE2 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.

Highlights

Varicose saphenous veins are characterized by venous backflow and blood stagnation. [1,2,3,4] This pathology is part of the chronic venous disease of the legs that is categorized into several classes from C0 to C6, where the C2 stage corresponds to varicose veins which are frequently removed by surgery. [5] Despite the high incidence of this disease, its pathogenesis is still poorly understood some hypotheses, such as a local hypertension or a genetic predisposition, have been suggested. [2,3].The metabolism and the effects of bioactive lipids like prostanoids (prostaglandins (PG) and thromboxane) has been rarely investigated in the context of varicose veins
In conclusion, PGE2 could be responsible for the vascular wall thickening in human varicose veins
Among the three PGE synthases (PGES) that catalyze the final step of PGE2 biosynthesis; two are constitutive: microsomal and cytosolic. [12,16] The third, mPGES-1, [11,12,16,17,18], is quantitatively the most important enzymatic activity for PGE2 production. mPGES-1 and COX-2 expression are generally co-induced by inflammatory cytokines such as IL-1b. [11,17] in a recent publication, [19] we have shown the absence of COX-2 in the varicose veins

Summary

Introduction

Varicose saphenous veins are characterized by venous backflow and blood stagnation. [1,2,3,4] This pathology is part of the chronic venous disease of the legs that is categorized into several classes from C0 to C6, where the C2 stage corresponds to varicose veins which are frequently removed by surgery. [5] Despite the high incidence of this disease, its pathogenesis is still poorly understood some hypotheses, such as a local hypertension or a genetic predisposition, have been suggested. [2,3].The metabolism and the effects of bioactive lipids like prostanoids (prostaglandins (PG) and thromboxane) has been rarely investigated in the context of varicose veins. [6] PGE2 via selective activation of EP1-4 receptor subtypes is involved in the control of vascular tone, [7,8] inflammation, [9,10,11,12] pain [13] and vascular wall remodeling. As observed during aneurysm formation or in the pathogenesis of endometriosis, [14,20,21,22] PGE2 modulates vascular wall remodeling mediated by the matrix metalloproteinases (MMPs). [14] On the other hand, MMP activities are under control of endogenous tissue inhibitor of metalloproteinase (TIMP) and changes in MMP/TIMP ratio are probably involved in vascular wall remodeling and in varicose vein formation. The renewal of extracellular matrix (ECM) by MMP [23] activity is dysregulated in many vascular diseases [24] such as acute coronary artery syndrome, atherosclerosis or aneurysm. [25,26,27,28,29] Some MMPs involved in these processes are the interstitial collagenase, MMP-1, that cleaves fibrillar collagens, which are subsequently degraded by the gelatinases, MMP-2 and MMP-9. [25,28] There are few studies in human tissues which have demonstrated the role of PGE2 on the expression/activation of MMPs. [14,20,21,22] For example, PGE2 activates several MMPs via EP2/EP4-receptor stimulation in human endometriotic epithelial and stromal cells. [14] On the other hand, MMP activities are under control of endogenous tissue inhibitor of metalloproteinase (TIMP) and changes in MMP/TIMP ratio are probably involved in vascular wall remodeling and in varicose vein formation. [30,31,32,33,34]

Results

Discussion

Conclusion