ATHEROGENIC LEVELS OF LOW-DENSITY-LIPOPROTEIN ALTER THE PERMEABILITY AND COMPOSITION OF THE ENDOTHELIAL BARRIER

In the present study we investigated the influence of elevated low den sity lipoprotein (LDL) concentration on endothelial permeability. Endo thelial cells were cultured on microporous membranes until confluence and albumin, dextran and LDL transfer across endothelial monolayers wa s determined to assess macromolecular permeability. Exposure of prolif erating aortic endothelial cells to LDL levels of more than 1 mg/ml LD L-cholesterol induced a concentration-dependent exponential increase i n the permeability of confluent endothelial monolayers. Acute addition of high LDL concentration did not alter macromolecular permeability. Once elevated permeability was induced, it persisted. It was not readi ly reversible after addition of normal LDL levels. Change in permeabil ity was accompanied by a selective decrease in basement membrane assoc iated heparan sulfate proteoglycan (HSPG) content. The apparent parall el between the loss in endothelial barrier function and HSPG decrease implicates a connection between the two events. Prolonged, but not acu te, incubation with antiserum directed against the core-protein of HSP G also led to increased permeability, suggesting a causal role of HSPG for the proper function of endothelium. The fact that non-atherogenic LDL-cholesterol levels had no effect indicates that a 'threshold' con centration for LDL-cholesterol may exist, leading to nondenuding injur y in the endothelial barrier as an early event in development of ather osclerosis.