Matrix metalloproteinase 2-induced venous dilation via hyperpolarization and activation of K+ channels: Relevance to varicose vein formation

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Abstract

Background:

Varicose veins are a common disorder of extensive venous dilation and remodeling with an as-yet unclear mechanism. Studies have shown increased plasma and tissue levels of matrix metalloproteinases (MMPs) in human varicose veins and animal models of venous hypertension. Although the effects of MMPs are generally attributed to extracellular matrix degradation, their effects on the mechanisms of venous contraction/relaxation are unclear. Our preliminary experiments have demonstrated that MMP-2 causes inhibition of phenylephrine-induced venous contraction. The purpose of this study was to determine whether MMP-induced inhibition of venous contraction involves an endothelium-dependent and/or -independent pathway.

Methods:

Circular segments of the inferior vena cava (IVC) were isolated from male Sprague-Dawley rats and suspended between two wire hooks in a tissue bath, and the effects of MMP-2 on phenylephrine- and KCl-induced contraction were measured. To study the role of endothelium-derived vasodilators, experiments were performed in the presence and absence of endothelium;NG-l-nitro-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthesis; indomethacin, an inhibitor of prostacyclin synthesis; cromakalim, an activator of adenosine triphosphate-sensitive K+ channels (KATP); and iberiotoxin, a blocker of large-conductance Ca2+-dependent K+ channels (BKCa) and smooth muscle hyperpolarization.

Results:

In endothelium-intact IVC segments, phenylephrine (10−5 mol/L) caused significant contraction that slowly declined to 82.0% in 30 minutes. The addition of MMP-2 (1 μg/mL) caused a gradual decrease of phenylephrine contraction to 39.5% at 30 minutes. In endothelium-denuded IVC, MMP-2 induced a greater reduction of phenylephrine contraction, to 7.6%. In the presence of l-NAME (10−4 mol/L), MMP-2 caused a marked decrease in phenylephrine contraction, to 4.4%. Large MMP-2-induced inhibition of phenylephrine contraction was also observed in IVC treated with l-NAME plus indomethacin. MMP-2 caused relaxation of phenylephrine contraction in IVC pretreated with cromakalim (10−7 mol/L), an activator of KATP channels. MMP-2-induced inhibition of phenylephrine contraction was abrogated in the presence of iberiotoxin (10−8 mol/L), a blocker of BKCa. MMP-2 did not inhibit venous contraction during membrane depolarization by 96 mmol/L KCl, a condition that prevents outward K+ conductance and cell hyperpolarization.

Conclusions:

MMP-2 causes significant IVC relaxation that is potentiated in the absence of endothelium or during blockade of endothelium-mediated nitric oxide and prostacyclin synthesis. The lack of effects of MMP-2 on KCl contraction and in iberiotoxin-treated veins suggests MMP-2-induced smooth muscle hyperpolarization and activation of BKCa channels—a novel effect of MMP that may play a role in the early stages of venous dilation and varicose vein formation.

Clinical Relevance:

The pathogenesis of varicose vein formation is unclear. Studies in humans suggest a possible role of MMPs in varicose vein formation and venous insufficiency. Also, studies in animal models of venous hypertension have demonstrated increased MMP levels in vein tissue and valve remodeling. However, there is no evidence of a causal relationship between venous MMP levels and varicose veins. Also, the implication of MMPs is based on an observed increase in their expression antecedent to or in association with the venous dilation, valve dysfunction, and tortuosity seen during varicose vein formation. Furthermore, a mechanistic model to study the role of MMPs in varicose vein formation is lacking. In this study, we demonstrate that MMP-2 causes relaxation of phenylephrine-contracted IVC segments by a mechanism involving hyperpolarization and likely activation of BKCa. In chronic conditions of venous hypertension, protracted MMP-2-induced venous relaxation could lead to progressive venous dilation, varicose vein formation, and chronic venous insufficiency.

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