HEPARIN INDUCES ENDOTHELIAL EXTRACELLULAR-MATRIX ALTERATIONS AND BARRIER DYSFUNCTION

We investigated the influence of heparin on the composition of the sub endothelial matrix and on endothelial permeability to elucidate the st ructure-function relationship of matrix composition and permeability. Albumin flux across the confluent endothelial monolayers was used to a ssess the macromolecular permeability. Lowest values were obtained whe n 100% serum was used as medium for permeability studies. The endothel ial matrix components, fibronectin and basement membrane-associated he paran sulfate proteoglycan (HSPG), were measured by enzyme immunoassay . Treatment of proliferating endothelial cells with heparin (0-900 mu g/ml) induced a dose-dependent decrease in endothelial HSPG content, w hereas the fibronectin content was unaltered. This structural change w as accompanied by an increase in albumin permeability. Both heparin ef fects exhibited similar dose-response curves with half-maximal effects at similar to 5 mu g/ml heparin. Acute addition of 300 mu g/ml hepari n had no effect on permeability or HSPG content. When endothelial cell s were preincubated with an HSPG antiserum, the endothelial permeabili ty increased nearly threefold. Our results indicate that heparin-induc ed loss of HSPG may cause the increase in endothelial permeability. Th e data underline the importance of HSPG for the integrity of the endot helial barrier.