Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins

Abstract

Chronic venous disease (CVD) is a common venous disorder of the lower extremities. CVD can be manifested as varicose veins (VVs), with dilated and tortuous veins, dysfunctional valves and venous reflux. If not adequately treated, VVs could progress to chronic venous insufficiency (CVI) and lead to venous leg ulcer (VLU). Predisposing familial and genetic factors have been implicated in CVD. Additional environmental, behavioral and dietary factors including sedentary lifestyle and obesity may also contribute to CVD. Alterations in the mRNA expression, protein levels and proteolytic activity of matrix metalloproteinases (MMPs) have been detected in VVs and VLU. MMP expression/activity can be modulated by venous hydrostatic pressure, hypoxia, tissue metabolites, and inflammation. MMPs in turn increase proteolysis of different protein substrates in the extracellular matrix particularly collagen and elastin, leading to weakening of the vein wall. MMPs could also promote venous dilation by increasing the release of endothelium-derived vasodilators and activating potassium channels, leading to smooth muscle hyperpolarization and relaxation. Depending on VVs severity, management usually includes compression stockings, sclerotherapy and surgical removal. Venotonics have also been promoted to decrease the progression of VVs. Sulodexide has also shown benefits in VLU and CVI, and recent data suggest that it could improve venous smooth muscle contraction. Other lines of treatment including induction of endogenous tissue inhibitors of metalloproteinases and administration of exogenous synthetic inhibitors of MMPs are being explored, and could provide alternative strategies in the treatment of CVD.

Vein morphometry in end-stage kidney disease: Teasing out the contribution of age, comorbidities, and vintage to chronic wall remodeling

“…Intimal hyperplasia and imbalanced ECM remodeling are histopathological changes associated with poor venous health ( 7 , 8 , 10 , 19 , 20 ). Kidney disease is considered a major contributing factor in the development of these vascular changes ( 2 , 3 , 5 , 21 ).…”

“…Intimal hyperplasia (IH) and imbalanced extracellular matrix (ECM) remodeling are implicated in the origin and progression of vascular diseases, and in postoperative complications after vascular surgeries ( 2 , 5 – 10 ). Concentric development of IH and moderate degree of wall fibrosis are frequently found in veins of CKD patients at the time of hemodialysis access creation ( 8 , 11 , 12 ).…”

In Vitro and In Vivo Characterization Methods for Evaluation of Modern Wound Dressings

“…Venous leg ulcers (VLUs) represent the most prevalent chronic wounds in the lower extremity of older patients with a recurrence rate of up to 70%. This type of ulcer results in damage of the superficial and deep venous system that progresses to venous insufficiency and 30–50% of patients fail to heal [ 40 , 41 ]. Venous ulcers are characterized by reduced blood flow, increased blood pressure, and the leakage of fibrin due to alteration of vessel wall permeability (endothelial dysfunction).…”

“…Venous ulcers are characterized by reduced blood flow, increased blood pressure, and the leakage of fibrin due to alteration of vessel wall permeability (endothelial dysfunction). The vascular dysfunction leads to excessive inflammation, increased levels of matrix metalloproteinases activity (MMP-1, 2, 9), redox imbalance (reactive oxygen and nitrogen species), reduced dispersion of oxygen, iron overload, shear stress, edema, and accumulation of tissue metabolites responsible for inadequate wound healing [ 41 , 42 , 43 ]. In another kind of a chronic wound, which normally occurs in old, paralyzed patients and people who are suffering from spinal cord injuries, deep tissue injuries limit blood flow to the surrounding tissue due to sustained stress and pressure in areas such as heels, sacrum, and shoulder blades.…”

Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence

“…Venous pathology could then progress through a vicious cycle of inflammation and leukocyte recruitment leading to further deteriorations. 5 , 7–9 …”