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Raffetto et al. Vessel Plus 2021;5:36 Vessel Plus
DOI: 10.20517/2574-1209.2021.16

Review Open Access

Mechanisms of lower extremity vein dysfunction in

chronic venous disease and implications in
management of varicose veins

Joseph D. Raffetto, Raouf A. Khalil

Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, and
Harvard Medical School, Boston, MA 02115, USA.
Correspondence to: Dr. Raouf A. Khalil, Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery,
Brigham and Women’s Hospital, and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
E-mail: raouf_khalil@hms.harvard.edu

How to cite this article: Raffetto JD, Khalil RA. Mechanisms of lower extremity vein dysfunction in chronic venous disease and
implications in management of varicose veins. Vessel Plus 2021;5:36. https://dx.doi.org/10.20517/2574-1209.2021.16

Received: 8 Feb 2021 Accepted: 10 May 2021 First online: 29 May 2021

Academic Editors: Rene Gordon Holzheimer, Markus Stücker Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

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.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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