Inhibition of cyclooxygenase activity by diclofenac attenuates varicose remodeling of mouse veins

Abstract

Aim: The development of varicose veins is driven by risk factors that support the progression of venous hypertension, specifically, by chronically augmenting the circumferential tension of the venous wall. We have previously verified the relevance of this biomechanical stimulus for the activation of venous cells and the structural remodeling of the vein wall. Recent transcriptome analyses revealed an increase in the expression of the gene encoding prostaglandin-endoperoxide synthase 2 [cyclooxygenase 2 (COX-2)] in biomechanically stressed human vein endothelial cells. This observation prompted us to investigate the functional relevance of COX activity for the onset of pressure-induced venous remodeling. Methods: For the in vitro experiments, isolated mouse veins were exposed to elevated intraluminal pressure levels to study the markers of cellular activation. For the in vivo experiments, pressure-dependent varicose remodeling of veins was induced by ligation of an efferent vein in the mouse auricle. Diclofenac was applied to inhibit the activity of COX. Results: Short-term exposure to elevated pressure levels stimulated the abundance of activated matrixmetalloproteinase-2 (MMP-2) and mitogen activated protein kinase, ERK1/2, in isolated mouse veins, which was inhibited upon treatment with diclofenac. Transdermal application of diclofenac-containing phospholipid-micelles attenuated the corkscrew-like enlargement of veins and decreased the abundance of COX-2 and MMP-2 as well as cell proliferation in the venous wall.

The genetic constituent of varicose vein pathogenesis as a key for future treatment option development

“…Does that mean all those efforts might be in vain? It is known that one of the most popular drugs in phlebological practice -micronized purified flavonoid fraction -is more effective as a complex substance rather than its components applied separately [73] . Nowadays, new possible venoactive drugs are being investigated.…”