Matrix metalloproteinases in the development of varicose disease

Abstract

Background: The imbalance between extracellular matrix components is a consequence of MMPs activity. Increased expression of matrix metalloproteinases (MMPs), in particular type 2 and 9, has been identified in varicose veins. MMP-2 and -9 have acute venodilatory effect in addition to their known effects on the extracellular matrix. The data suggest that protracted increases in venous pressure and wall tension increase MMPs expression, which in turn reduce venous contraction and lead to progressive venous dilation. Increases in magnitude and duration of wall tension are associated with reduced contraction and overexpression of MMP-2 and -9. MMP-2 and -9 promote inferior vena cava relaxation. MMP-2 did not inhibit venous contraction during membrane depolarization by high KCl, suggesting that MMP-2 induced relaxation likely involves hyperpolarization and activation of a K channel. MMPs cause hyperpolarization of the smooth muscle cells of the vein wall, leading to prolonged opening of Ca2 -dependent K channel (BKCa). Conclusions: MMP-2 causes significant inhibition of Phenylephrine and Angiotensin II-induced IVC contraction likely through a post-receptor mechanism involving activation of plasmalemmal K channels, membrane hyperpolarization, and inhibition of Ca2 influx. MMP-2 induced inhibition of the Ca2 entry mechanism of venous smooth muscle contraction may play a role in the venous dilation associated with varicose vein formation. Studying the mechanisms of action of MMPs is an important step in the development of new treatment methods of varicose veins, such as synthetic inhibitors of matrix metalloproteinases.