Extracellular Matrix Remodeling in Response to Venous Hypertension: Proteomics of Human Varicose Veins

Aims: Extracellular matrix remodeling has been implicated in a number of vascular conditions, including venous hypertension and varicose veins. However, to date no systematic analysis of matrix remodeling in human veins has been performed. Methods and Results: To understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix. Varicose saphenous veins removed during phlebectomy and normal saphenous veins obtained during coronary artery bypass surgery were collected for proteomics analysis. Extracellular matrix proteins were enriched from venous tissues. The proteomics analysis revealed the presence of more than 150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue. Extracellular matrix remodeling in varicose veins was characterised by a loss of aggrecan and several small leucine-rich proteoglycans and a compensatory increase in collagen I and laminins. Gene expression analysis of the same tissues suggested that the remodeling process associated with venous hypertension predominantly occurs at the protein rather than the transcript level. Loss of aggrecan in varicose veins was paralleled by a reduced expression of aggrecanases. Chymase and tryptase ß1 were among the upregulated proteases. The effect of these serine proteases on the venous extracellular matrix was further explored by incubating normal saphenous veins with recombinant enzymes. Proteomics analysis revealed extensive extracellular matrix degradation after digestion with tryptase ß1. In comparison, chymase was less potent and degraded predominantly basement membrane-associated proteins. by gest on A ril 8, 2016 D ow nladed fom