Sulodexide Improves Contraction and Decreases Matrix Metalloproteinase-2 and -9 in Veins Under Prolonged Stretch

Abstract

High pressure in the lower-limb veins is often associated with chronic venous insufficiency and varicose veins (VVs), making it important to search for the mechanisms and agents that control venous function. We have shown that protracted increases in venous stretch/wall tension reduce vein contraction and augment matrix metalloproteinase (MMP)-2 and -9. Also, MMP-2 and MMP-9 promote venodilation, a hallmark of VVs. Sulodexide (SDX) is a blend of glycosaminoglycans with efficient profibrinolysis and antithrombosis activities, but its actions on vein function and the mechanisms involved are unclear. We tested the hypothesis that SDX enhances venous contractile response by decreasing MMP expression/activity in veins subjected to protracted stretch. Rat inferior vena cava (IVC) rings were treated with SDX (0.001–1 mg/mL) or vehicle, equilibrated under control 0.5-g resting tension or protracted 2-g stretch for 18 hours, and the contractile response to 96-mM KCl and phenylephrine (Phe) in SDX-treated and nontreated veins was recorded. In IVC rings under control 0.5-g resting tension, SDX caused dose-dependent contraction, 96-mM KCl caused marked contraction (176-mg/mg tissue), and Phe caused dose-dependent contraction with a maximum (56-mg/mg tissue) at 10−5 M. In IVC subjected to protracted 2-g stretch, 96-mM KCl-induced contraction was reduced to 112 mg/mg and maximal Phe-induced contraction was decreased to 23 mg/mg. In IVC subjected to protracted 2-g stretch plus SDX, 96-mM KCl-induced contraction was restored to 228 mg/mg and maximal Phe-induced contraction was improved to 115 mg/mg. Gelatin zymography and Western blots revealed increases in MMP-2 and MMP-9 levels/gelatinolytic activity in veins subjected to protracted 2-g stretch and reversal to control levels in veins subjected to 2-g stretch plus SDX. Thus, SDX improves vein function and augments the contractile response in veins subjected to protracted stretch. The SDX-induced improvement of contraction and restoration of vein function appear to involve decreases in MMP-2 and MMP-9 and may contribute to the benefits of SDX in chronic venous insufficiency and VVs.

Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment

“…Sulodexide’s effect on venous contraction was partly due to an increase in the sensitivity of the α-adrenergic receptor, but likely, sulodexide also enhanced downstream mechanisms (Ca 2+ sensitivity and mobilization, PKC, MAPK, and Rho-kinase). These novel mechanism in SDX vein contraction may be important not only in venous leg ulcers but also in treating CVD in general and improving venous function [ 170 , 171 ].…”

Tissue remodelling and increased DNA damage in patients with incompetent valves in chronic venous insufficiency

“… 14 The structural and functional diversity of MMPs rival those of the collagen superfamily, and MMP‐2 has a prominent role in vascular remodelling. 15 , 16 , 17 The proteolytic activity of MMP‐2 is regulated at three levels: first—via expression and secretion; second—through pro‐enzyme activation and third—through inhibition by tissue inhibitors of MMPs (TIMPs). This regulation serves to maintain a delicate balance.…”

Systematic literature review and network Meta-analysis of sulodexide and other drugs in chronic venous disease

“…4,122,123 Besides accelerating the epithelialization of refractory trophic ulcers, protects the endothelium, preventing endothelial venous cell apoptosis and inhibiting the release by endothelial cells of reactive oxygen species (ROS) and pro-inflammatory chemokines and interleukins, sulodexide also is able to inhibit MMPs with cysteine residues such as MMP-2 and MMP-9 as in-vitro and in-vivo experiments have shown. 16,124–126 The above mentioned properties of sulodexide together with hemodynamic properties allow patients treated with sulodexide to have improved CVD symptoms and achieve healing of venous ulcers. 12,112,127–131 The meta-analysis of observational studies reported in this work (Supplementary Appendix 4, Figures 1 to 8), as already shown in previous studies, 15 confirmed the expected effectiveness of sulodexide in improving symptoms, signs and indirectly the quality of life of patients with CVD.…”

“…15 In addition, a new experimental study in rats demonstrated that sulodexide increased contractility and restoration of vein function inducing decrease of MMP-2 and MMP-9 endothelial levels after prolonged stretch. 16…”