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 density lipoprotein (LDL) concentration on endothelial permeability. Endothelial cells were cultured on microporous membranes until confluence and albumin, dextran and LDL transfer across endothelial monolayers was determined to assess macromolecular permeability. Exposure of proliferating aortic endothelial cells to LDL levels of more than 1 mg/ml LDL-cholesterol induced a concentration-dependent exponential increase in 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 readily reversible after addition of normal LDL levels. Change in permeability was accompanied by a selective decrease in basement membrane associated heparan sulfate proteoglycan (HSPG) content. The apparent parallel between the loss in endothelial barrier function and HSPG decrease implicates a connection between the two events. Prolonged, but not acute, incubation with antiserum directed against the core-protein of HSPG 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' concentration for LDL-cholesterol may exist, leading to nondenuding injury in the endothelial barrier as an early event in development of atherosclerosis.