Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins

Abstract

Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane- type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. Endothelial cell injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.

Fig. 1

Parthophysiology and management of CVD. In the presence of genetic and environmental risk factors, increases in lower extremity venous hydrostatic pressure could cause valve dysfunction and venous reflux as well as increased wall tension, and increased expression/activity of MMPs. In addition to degradation of extracellular matrix (ECM) proteins, MMPs may cause venous smooth muscle (VSM) hyperpolarization and activation of K⁺ Channels, which in turn could cause inhibition of Ca²⁺ entry through voltage-gated Ca²⁺ channels (VGCC), VSM relaxation, vein wall dilation, and early manifestations of chronic venous disease (CVD). Persistent increases in venous pressure could cause ECs injury, leukocyte infiltration and inflammation of the vein wall, which could further increase MMPs expression/activity and lead to vein wall remodeling and tortuosity and late manifestations of chronic venous insufficiency (CVI). Several pharmacological and surgical approaches (presented in block arrows) are used for treatment of early and late manifestations of CVD. Different classes of MMP inhibitors may provide a new approach for management of CVD.

Fig. 2

Early and late manifestations of CVD. In normal veins with intact valves, blood flows from superficial to deep femoral vein. Increases in lower extremity venous hydrostatic pressure and vein wall tension are associated with increased MMP expression/activity, venous dilation and venous reflux and early manifestations of CVD such as edema and spider veins. Late stages of CVD are associated with further increases in MMPs, varicose veins, edema, vein tissue remodeling, inflammation and fibrosis. CVI is complicated by thrombophlebitis, further increases in ROS, and venous wound leg ulcer.

Fig. 3

Major classes and structure of matrix metalloproteinase. Typically, MMPs consist of a propeptide of about 80 amino acids, a catalytic metalloproteinase domain of about 170 amino acids, a linker peptide (hinge region) of variable lengths and a hemopexin domain of about 200 amino acids. The catalytic domain contains the Zn²⁺ binding motif HEXXHXXGXXH. Matrilysins are exceptions as they lack the linker peptide and the hemopexin domain. Membrane-bound MMPs (MT-MMPs) have a furin-like proprotein convertase recognition sequence at the C-terminus of the propeptide and some of them have a glycosylphosphatidylinositol (GPI) anchor.