fig2

Figure 2. Pathophysiology and management of CVD. Genetic, environmental and behavioral risk factors cause an increase in HIFs and tissue metabolites leading to increases in MMPs. Increased venous hydrostatic pressure also causes changes in shear stress, endothelial dysfunction, glycocalyx injury, increased permeability, leukocyte infiltration, and increased adhesion molecules, inflammatory cytokines, ROS, and RNS, leading to further increases in MMPs. Increased MMPs cause VSM hyperpolarization and relaxation as well as ECM degradation leading to vein wall dilation, and progressive increases in venous hydrostatic pressure (vicious cycle). Increased MMPs generally promote ECM degradation particularly in atrophic regions. Other theories (indicated by interrupted arrows) suggest a compensatory anti-inflammatory pathway involving prostaglandins and their receptors that leads to decreased MMPs, ECM accumulation in hypertrophic regions, and tortuous VVs. Increased venous hydrostatic pressure in the lower extremity saphenous and femoral veins also causes venous valve dysfunction and venous reflux. Progressive vein wall dilation and valve dysfunction lead to different stages of CVD and CVI. Current treatment (presented in shaded arrows) includes compression stockings, venotonics and other pharmacological and surgical approaches. MMP inhibitors (also presented in shaded arrows) may provide potential tools for the management of CVD/CVI. CVD: Chronic venous disease; HIFs: hypoxia inducible factors; MMPs: matrix metalloproteinases; VSM: vascular smooth muscle; ECM: extracellular matrix; VVs: varicose veins; CVI: chronic venous insufficiency; TIMPs: tissue inhibitors of metalloproteinases; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1; siRNA: small interfering RNA; ROS: reactive oxygen species; RNS: reactive nitrogen species; SDX: sulodexide.