Biomechanical stretch triggers varicose vein remodeling in mice through activation of the transcription factor AP‐1

Varicosis is the most common cause of chronic venous insufficiency and develops due to dysfunctional valves that reduce venous return and increases venous filling pressure. Although this medical condition represents a substantial source of morbidity in industrialized countries, the cellular mechanism(s) underlying the development of varicosis are poorly understood. To decipher such mechanisms controlling, e.g. changes in smooth muscle cell (SMC) proliferation, gelatinolytic activity and expression of matrix metalloproteinase 2 (MMP‐2) in human varicose veins, we established a mouse model of venous remodeling by ligating one large vein in the mouse auricle. The subsequent rise in pressure led to a tortuous enlargement of the collateral veins which was accompanied by proliferation of endothelial and smooth muscle cells, and expression of MMP‐2. Treatment of the auricles with decoy oligonucleotides neutralizing the transcription factor activator protein 1 (AP‐1) inhibited this remodeling process. Likewise, proliferation, MMP‐2 expression and gelatinolytic activity of the endothelial and smooth muscle cells in isolated pressure‐perfused veins or in stretch‐stimulated cultured human SMCs were blunted by inhibiting AP‐1 activity. Based on these findings we conclude that the onset of venous hypertension activates AP‐1 and triggers varicose remodeling inter alia by controlling MMP‐2 activity.