We recently reported that an increase in wall stress is sufficient to trigger maladaptive varicosis-like venous remodeling processes which are dependent on the activation of the mechanosensitive transcription factor activator protein-1 (AP-1). Considering that statins - a widely used class of drugs lowering blood cholesterol - are discussed to block AP-1 activity, this study consequently investigates the putative inhibitory impact of these drugs on venous remodeling processes.

To this end, we utilized a novel auricle vein ligation mouse model in which an increase of the local filling pressure induces varicose-like remodeling of collateral veins. In this model, the effect of drugs - topically applied on the mouse auricle or systemically administered as a diet supplement - on maladaptive venous remodeling was analyzed. To mimic the increase in venous wall stress in vitro, human umbilical vein smooth muscle cells (HUVSMC) were cyclically stretched using the BioFlex-culture-system.

Based on these experimental setups, we show that statins inhibit the activity of AP-1 in stretch-stimulated HUVSMC as evidenced by electrophoretic mobility shift assay. Moreover, stretch-induced up-regulation of the expression of MCP-1 - an AP-1 target gene - in these cells could be blocked by Rosuvastatin (RVS) and this was reversed by Mevalonate. In vivo, systemic administration of Atorvastatin (AVS) or RVS robustly inhibits venous remodeling. Comparable effects were evoked upon transdermal application of AP-1-neutralizing decoy oligodeoxynucleotides which inhibited proliferation of endothelial and smooth muscle cells.

In summary, our study suggests that statins inhibit varicosis-like venous remodeling by promoting a decline in wall-stress-mediated activity of AP-1.