Venous Tone is a Critical Determinant of Venous Valve Closure in the Mouse

Venous diseases commonly involve venous wall and/or valve dysfunction. Chronic venous dilation, a characteristic of varicose veins, can progress to the point where venous valve (VV) leaflets are pulled sufficiently apart that they no longer prevent back flow. Incompetent VVs increase the load on more distal valves by increasing the standing column of proximal blood. We tested VV function by isolating single valves from cervical veins of the mouse and measuring back leak and the adverse pressure gradient required for closure. Valve identification was facilitated by genetically forced expression of GFP in VV endothelium. A causal relationship was found between the relative diameter of the vein and VV closure, with a striking effect of venous tone: ∼60% of mature VVs in the cervical vein were incapable of closing if the vessel lost spontaneous tone and, in another ∼20% of veins, VVs closed only when venous tone exceeded some threshold value. Our results have important implications for the causes and possible treatment of VV incompetence in pathological states such as venous varicosity and chronic venous insufficiency. Moreover, they suggest an underappreciated mechanism whereby loss of venous tone can initiate a feed-forward cycle of events that make valve closure increasingly difficult, thereby elevating local venous pressure and exacerbating the loss of tone. This detrimental cycle may potentially be interrupted by appropriate pharmacological therapy to enhance venous tone and thereby restore VV competence.