title: Decreased PGE₂ content reduces MMP-1 activity and consequently increases collagen density in human varicose vein.
abstract: Varicose veins are elongated and dilated saphenous veins. Despite the high prevalence of this disease, its pathogenesis remains unclear.
  
  
  OBJECTIVE
  In this study, we investigated the control of matrix metalloproteinases (MMPs) expression by prostaglandin (PG)E₂ during the vascular wall remodeling of human varicose veins.
  
  
  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 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.
  
  
  CONCLUSIONS
  In 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.
authors: INSERM, U698, Paris, France ; University Paris Nord, UMR-S698, Paris, France.
authors: Ingrid
authors: I
authors: Gomez
authors: INSERM, U698, Paris, France ; University Paris Nord, UMR-S698, Paris, France.
authors: Chabha
authors: C
authors: Benyahia
authors: INSERM, U698, Paris, France.
authors: Liliane
authors: L
authors: Louedec
authors: INSERM, U698, Paris, France ; AP-HP CHU X. Bichat, Department of Vascular and Thoracic Surgery, University Paris Diderot, Sorbonne Paris-Cité, UMR-S698, Paris, France.
authors: Guy
authors: G
authors: Leséche
authors: INSERM, U698, Paris, France.
authors: Marie-Paule
authors: MP
authors: Jacob
authors: INSERM, U698, Paris, France ; AP-HP CHU X. Bichat, Department of Anesthesia and Intensive Care, University Paris Diderot, Sorbonne Paris-Cité, UMR-S698, Paris, France.
authors: Dan
authors: D
authors: Longrois
authors: INSERM, U698, Paris, France ; University Paris Nord, UMR-S698, Paris, France.
authors: Xavier
authors: X
authors: Norel
mesh_terms: D000368:Aged; D003094:Collagen / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014648:Varicose Veins / Q000378:metabolism* / Q000473:pathology
chemical_list: D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone