Published Online
on July 15, 2002

A more recent version of this article appeared on July 30, 2002

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Submitted on April 24, 2002
Revised on June 10, 2002
Accepted on June 10, 2002

Plasma Matrix Metalloproteinase-9 as a Marker of Blood Stasis in Varicose Veins

Marie-Paule Jacob PhD^*, Michèle Cazaubon MD, Anthony Scemama MD, Dominique Prié MD, PhD, Françoise Blanchet MD, Marie-Claude Guillin MD, PhD, and Jean-Baptiste Michel MD, PhD

From INSERM U460 (M.-P.J., J.-B.M.), Service d'explorations fonctionnelles (M.C., D.P., F.B.), and INSERM E9907 and Service d'Hématologie et Immunologie (A.S., M.-C.G.), CHU Xavier Bichat, Paris, France.

^* To whom correspondence should be addressed. E-mail: jacob{at}bichat.inserm.fr.

Background—Possible intermediate circulating markers linking blood stasis to vein remodeling were explored in patients with varicose veins in the lower limbs.

Methods and Results—Blood was sampled at rest (supine position) and after a stasis of 30 minutes both in the varicose vein (limbs hanging down) and in the brachial vein (arm hanging down) as a paired control. Several endothelial and leukocyte markers were measured in plasma with the use of ELISA kits. Angiotensin-converting enzyme activity was determined by use of a specific substrate. Matrix metalloproteinases (MMPs) 9 and 2 were evaluated with the use of gelatin zymography. No markers were significantly modified after 30 minutes of blood stasis in the brachial vein. After 30 minutes of blood stasis in the varicose vein, oxygen partial pressure decreased (P<0.01). Although thrombomodulin, von Willebrand factor, vascular endothelial growth factor, and MMP-2 were not modified in these conditions, the proteins released by proteolysis from the endothelial membrane intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and angiotensin-converting enzyme were increased (P<0.01). After blood stasis in varicose veins, the leukocyte markers lactoferrin, myeloperoxidase, and interleukin-8 were not modified, whereas L-selectin shed from leukocytes increased (P<0.05), and a major increase in pro-MMP-9, which is released from tertiary granules during polymorphonuclear activation, was observed (P=0.0001).

Conclusions—The marked increase in plasma pro-MMP-9 activity provides evidence of polymorphonuclear activation and granule release in the varicose vein in response to postural blood stasis. Similarly, detection in the plasma of membrane proteins shed from the endothelium or leukocytes provides evidence of pericellular proteolysis.

Key words: cell adhesion molecules • angiotensin-converting enzyme • metalloproteinases • plasma • hypoxia

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