Background: 

Varicosis is the most common vein disease and develops due to pathophysiological remodeling of the venous wall. Although it represents a substantial source of morbidity in industrialized countries, the underlying cellular mechanism(s) are poorly understood.

Methods and Results: 

Based on immunofluorescence analyses, we identified an increase in smooth muscle cell (SMC) proliferation, expression of matrix metalloproteinase-2 (MMP-2) and elevation of gelatinolytic activity as the most pronounced changes in human varicose veins. To decipher mechanisms controlling these activities, we established a mouse model of venous remodeling by ligating one large vein in the mouse ear. The subsequent rise in hydrostatic pressure as a result of the outflow obstruction led to a tortuous enlargement of the collateral veins that was accompanied by the proliferation of both endothelial cells and SMCs, and expression of MMP-2. Topical treatment of the ears with decoy oligonucleotides neutralizing the transcription factor activator protein 1 (AP-1) - a prototypic mediator of vascular responses elicited by a rise in circumferential wall tension (CWT) - strongly attenuated this remodeling process. Likewise, proliferation, MMP-2 expression and gelatinolytic activity of both endothelial cells and SMCs in isolated pressure-perfused mouse veins or in stretch-stimulated human cultured venous SMCs were essentially blunted by inhibiting AP-1 activity.

Conclusions: 

Our findings indicate that a volume-dependent rise in hydrostatic pressure in veins activates AP-1 through the resulting increase in CWT and thus triggers their varicose remodeling inter alia by controlling MMP-2 activity and SMC proliferation. This mechanism is sufficient to orchestrate the onset of varicose remodeling and consequently may be both cause and consequence of venous valve dysfunction or primary vein wall weakening.