In this issue of the Journal of Cardiovascular Pharmacology, Raffetto et al, 1 by using ex-vivo animal models, explored the involvement of protracted venous stretch and wall tension to decrease vein contraction, demonstrating that this could be associated to an altered expression and activity of the gelatinolytic enzymes matrix metalloproteinase (MMP)-2 and -9. Also, MMP-2 and MMP-9 p. Also, MMP-2 and MMP-9 promote venodilation, a hallmark of varicose veins (VV). Notably, they described the ability of sulodexide (SDX) to promote venous contraction in a concentration-dependent fashion and to restore the contractile functions lost by veins subjected to protracted stretch. Raffetto et al highlighted that the increased levels and gelatinolytic activity of MMP-2 and MMP-9, accompanying the loss of contractile function induced by stretch, are significantly reduced by SDX treatment.1
This experimental model was selected to simulate the role of venous hypertension during chronic venous disease (CVeD).
CVeD is a common disease of the lower extremities, which has relevant physical, psychological, and socioeconomic impact. Venous disorder is the result of an intricate series of events encompassing hemodynamic dysfunctions, alteration of vein structures (muscular pump dysfunction and valvular incompetence) and dysregulation of biochemical pathways, which overall impair the peripheral blood return to the heart, promote blood pooling and increase venous pressure within the lower extremities. The list of predisposing factors able to promote venous hypertension (including advanced age, female sex, genetic predisposition, family history, pregnancy, estrogen levels, obesity, prolonged standing, sitting, environmental/occupational factors) has lengthened throughout the last years.2
According to the CEAP (clinical, etiological, anatomical, and pathophysiological) classification, the pathogenic mechanisms of CVeD include venous reflux, obstruction, or both, which give rise to the major finding observed in all the CVeD phases, represented by ambulatory venous hypertension. Once venous hypertension is transmitted to the skin, clinical signs of CVeD appear in the legs. Clinical manifestations start from telangiectasias and VVs, to more advanced signs (eg, edema, skin changes, and venous ulcerations) which are preferentially defined with the term of Chronic Venous Insufficiency (CVI).
The current knowledge on the pathogenic mechanisms underlying the development of CVeD highlights a crucial role and an intricate network among endothelial dysfunction, inflammatory processes and proteolytic imbalance, which overall are fed each other. Despite these cellular and biochemical alterations are strictly linked to hemodynamic modifications, a unified pathogenetic theory is still lacking. Any improvement in the understanding of the pathophysiological mechanisms of CVeD will pave the way for the identification of potential biomarkers of disease progression, as well as therapeutic targets.
In this respect, an increasing interest has been aroused by venoactive drugs, for their ability to both improve the venous tone and contractility, and restore the inflammatory and proteolytic balance within the tissue.
The crucial role of MMP in CVeD is witnessed by an increasing number of pieces of evidences ranging from studies on venous tissue and body fluids both in human and animal models. In fact, the pathological remodeling of vein walls and valves observed in CVeD is sustained by an intense and unbalanced expression and activity of various MMPs. However, despite a widespread agreement on the proteolytic unbalance characterizing the different CVeD phases, the upstream causes promoting MMP overexpression and the downstream pathways involved in MMP-induced vein wall remodeling still remain a matter of debate. Several mechanisms have been proposed to underlie the involvement of MMP in CVeD, including genetic polymorphisms, increased expression, protein imbalance between MMP and their tissue inhibitors (TIMP). The current investigation by Raffetto et al adds another piece to the complex jigsaw puzzle on the role of MMP in CVeD. In fact, the observation that experimental mechanical stretchs on vein walls trigger the release of MMP from the veins, may provide the biochemical trait d'union between hemodynamic alterations and clinical manifestations of CVeD. This observation is confirmed by studies sustaining that the restoration of hemodynamic function performed by compressive treatments is also promoted by an amelioration of the proteolytic balance.3
If the usefulness of MMPs as diagnostic and prognostic target seems to be a goal achievable not so far, their use as specific therapeutic target needs more investigations. To date, the only U.S. Food and Drug Administration (FDA)–approved MMP inhibitor is Periostat, a doxycycline-based treatment developed for periodontal disease, which acts as non-specific inhibitor of MMPs. However, several clinical trials are currently investigating MMP inhibitors for the treatment of gastric cancer, multiple sclerosis, and diabetic foot ulcers, providing demonstrations that the potential use of MMP inhibitors in clinical practice could be a goal of the next future.4
The challenge of MMP inhibitors in CVeD must take into account that the role of MMPs is multifunctional, and may be either detrimental or beneficial on the basis of the ratio with their inhibitors, and this balance could modify during the course of disease. Therefore, targeting specific MMP, in a time-controlled and tissue-specific manner, controlling excessive proteolytic activity in determined steps, but maintaining their role when needed, are features that should be addressed.
In this respect, SDX is a pharmacological agent composed of a mixture of 2 glycosaminoglycans (80% of fast-moving heparin fraction and 20% of dermatan sulfate) that overall account for a wide array of beneficial vascular effects.5 SDX's pleiotropic biological effects, including reduction of venous and arterial thrombogenesis, anti-inflammatory properties, and endothelial cell-protection, corroborate to its clinical applications. In fact, SDX is characterized by a remarkable ability to be absorbed to the vascular endothelium, where it exerts an anti-thrombotic activity, restores the glycocalyx and endothelial cell permeability, modulates inflammatory and proteolytic processes and regulates blood cell interactions with the endothelium5,6 (Fig. 1).
The ability of SDX to modulate the release of specific MMP classes has been explored both in preclinical and clinical studies on cardiovascular disorders, affecting MMP secretion and proteolytic activity through various mechanisms, including direct interaction with MMPs, decreasing their synthesis, or interference with the signaling cascade that is activated by inflammatory stimuli.7–9
In this respect, Raffetto et al tested a wide range of concentrations of SDX (0.001–1 mg/mL) in their experimental research. These doses were selected according to the pharmacokinetics properties of SDX in human studies and to its solubility. On the other hand, MMP inhibition, which is obtained at different concentration for different MMP, needs to take into consideration the dose-limiting side effects of inhibitors.
Emerging roles for SDX are being discovering during the last years, which are broadening the horizons for the use of SDX in other vascular disorders. Intriguing results range from the ability of SDX to reduce the risk of recurrence in patients with venous thromboembolism10 to the inhibition of the uptake of electronegative LDL (LDL (−)) from monocytes and the modulation of the proteolytic pathways activated by LDL (−).9 Such a novel properties warranted further studies to investigate the potential role of SDX in both arterial and venous disorders.
New frontiers for SDX have been also explored by the research article by Raffetto et al 1 demonstrating that SDX can act against both venous hypertension and dysregulated MMP activity, common hallmarks of all CVeD stages, making SDX a candidate drug suitable for the treatment of both the early and the advanced phases of CVeD.
Despite the signaling pathways underlying SDX pleiotropic effect still remain opened questions, even more biochemical and physiological pieces of evidences support its clinical benefits. Further efforts are warranted to improve the knowledge on the biological and pharmacological effects of SDX to render it a promising weapon to face CVeD since the first clinical signs of venous hypertension.
1. Raffetto JD, Yu W, Wang X, et al. Sulodexide improves contraction and decreases matrix metalloproteinase-2 and -9 in veins under prolonged stretch. J Cardiovasc Pharmacol. 2019 [epub ahead of print].
2. Mansilha A, Sousa J. Pathophysiological mechanisms of chronic venous disease and implications for venoactive drug therapy. Int J Mol Sci. 2018;19:1669.
3. Lattimer CR, Fareed J, Hoppensteadt D, et al. Validation of a gravitational model to study local endogenous biomarkers in chronic venous insufficiency. Eur J Vasc Endovasc Surg. 2018;56:865–873.
4. Fields GB. The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells. 2019;8:pii:E984.
5. Carroll BJ, Piazza G, Goldhaber SZ. Sulodexide in venous disease. J Thromb Haemost. 2019;17:31–38.
6. Coccheri S, Mannello F. Development and use of sulodexide in vascular diseases: implications for treatment. Drug Des Devel Ther. 2013;8:49–65.
7. Ligi D, Mosti G, Croce L, et al. Chronic venous disease—part II: proteolytic biomarkers in wound healing. Biochim Biophys Acta. 2016;1862:1900–1908.
8. Urbanek T, Zbigniew K, Begier-Krasińska B, et al. Sulodexide suppresses inflammation in patients with chronic venous insufficiency. Int Angiol. 2015;34:589–596.
9. Ligi D, Benitez S, Croce L, et al. Electronegative LDL induces MMP-9 and TIMP-1 release in monocytes through CD14 activation: inhibitory effect of glycosaminoglycan sulodexide. Biochim Biophys Acta Mol Basis Dis. 2018;1864:3559–3567.
10. Andreozzi GM, Bignamini AA, Davì G, et al. Sulodexide for the prevention of recurrent venous thromboembolism: the sulodexide in secondary prevention of recurrent deep vein thrombosis (SURVET) study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation. 2015;132:1891–1897.