Matrix Metalloproteinases in Remodeling of Lower Extremity Veins and Chronic Venous Disease

Abstract

The veins of the lower extremity are equipped with efficient wall, contractile venous smooth muscle (VSM) and competent valves in order to withstand the high venous hydrostatic pressure in the lower limb and allow unidirectional movement of deoxygenated blood towards the heart. The vein wall structure and function are in part regulated by matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases that are secreted as inactive proMMPs by different cells in the venous wall including fibroblasts, VSM and leukocytes. ProMMPs are activated by other MMPs, proteinases, and other endogenous and exogenous activators. MMPs degrades various extracellular matrix (ECM) proteins including collagen and elastin, and could affect other cellular processes including endothelium-mediated dilation, VSM cell migration and proliferation as well as modulation of Ca2+ signaling and contraction in VSM. It is thought that increased lower limb venous hydrostatic pressure increases hypoxia inducible factors and other MMP inducers such as EMMPRIN, leading to increased MMP expression/activity, ECM protein degradation, vein wall relaxation, and venous dilation. Vein wall inflammation and leukocyte infiltration cause additional increases in MMPs, and further vein wall dilation and valve degradation, that could lead to chronic venous disease and varicose veins (VVs). VVs are often presented as vein wall dilation and tortuosity, incompetent venous valves and venous reflux. Different regions of VVs show different MMP levels and ECM proteins with atrophic regions showing high MMP levels/activity and little ECM compared to hypertrophic regions with little or inactive MMPs and abundant ECM. Treatment of VVs includes compression stockings, venotonics, sclerotherapy or surgical removal. However, these approaches do not treat the cause of VVs, and other lines of treatment may be needed. Modulation of endogenous tissue inhibitors of metalloproteinases (TIMPs), and exogenous synthetic MMP inhibitors may provide new approaches in the management of VVs.

Validation of a Gravitational Model to Study Local Endogenous Biomarkers in Chronic Venous Insufficiency

“…The aim of this proof of concept study was to evaluate a gravitational model of venous insufficiency using two inflammatory biomarkers of cell damage, 4,5 as well as the matrix metalloproteinases (MMPs), which are pivotal in tissue remodelling, 6,7 and as regulators of inflammation. 8 Stationary standing was used as a state of stress, and leg elevation and medical compression stockings as recovery states.…”

Microcirculation Evaluation of Leg Ulcers - An Innovative Diagnostic Approach

“…systems able to perpetuate the Chronicity of inflammation, and further acquisitions on cellularity (chemo-taxis, macrophages and monocytes) demonstrate their complex interconnection that makes it still difficult to univocally explain the processes involved respectively at the cellular level, intercellular and with the extracellular matrix [5][6][7]. Biofilms, ROS / NOS systems [8][9][10][11][12][13], microvesicles [14,15], metalloproteases [3][4][5] and other factors have been examined and are sometimes held responsible for the transformation of the acute inflammatory state into chronic [14][15][16][17][18][19][20].…”

Chronic venous disorders: from macrocirculation to microcirculation

“…Vein wall remodelling is likely to involve the complex interplay of a range of factors, including an altered ratio between metalloproteinases (MMPs), particularly MMP9, and their tissue inhibitors (TIMPs), and elevated levels of cytokines and growth factors favour an alteration of the extracellular matrix. Neutrophils and mast cells and their interaction with the venous endothelium are believed to play an important role in the initiation of the inflammatory response in CVD 3,4 .…”

“…Venous wall distension may also result in the increase of other MMPs inducers, such as EMMPRIN (extracellular matrix metalloproteinase inducer), hormones and NGAL (neutrophil gelatinase-associated lipocalin) 4 . High levels of MMPs activate specific protease receptors on endothelial cells, leading to a reduced endothelial production of Nitric Oxide (NO), which inhibits VSM contraction and stimulates venous dilatation.…”

“…The activity of the MMPs further supports venous dilatation through the release of growth factors (such as TGF beta, VGF, FGF), which stimulate VSM hypertrophy. The hyperactivity of the MMPs finally degrades the ECM, triggering a mechanism of migration of the SMC, with further dilation of the venous wall and the consequent establishment of varicose veins 3,4 .…”