Low density lipoprotein transport across a microvascular endothelial barrier after permeability is increased

Abstract

We investigated the pathways for low density lipoprotein (LDL) transport across an endothelial barrier in individually perfused microvessels before and after an increase in permeability. The divalent cation ionophore A23187 (5 μM) was used to increase microvessel permeability. LDL permeability coefficients (Ps(LDL)) were measured using quantitative fluorescence microscopy. In the control state, Ps(LDL) measured after 10-23 minutes of accumulation of fluorescent-labeled LDL outside the microvessel wall was 4.8 x 10-8 cm/sec. The transvascular vesicular exchange of approximately 50 vesicles/sec would account for the measured flux. The flux of LDL across the microvessel wall increased as much as 170-fold at the peak of the permeability increase (2-4 minutes after ionophore infusion). Permeability returned toward control values 10 minutes after ionophore infusion but remained elevated for as long as ionophore was present in the perfusate. The effective Ps(LDL) was similar in magnitude to the Ps for fluorescent-labeled dextran (MW 20,000) when permeability was increased. To investigate the nature of pathways for LDL in the high-permeability state, Ps(LDL) was measured at a series of microvessel pressures. LDL transport increased as microvessel pressure increased, demonstrating coupling of LDL flux to transvascular water flow. Solvent drag accounted for more than 95% of the increased flux of LDL in the period 2 - 10 minutes after permeability increased. Our results conform to the hypothesis that porous pathways between adjacent enothelial cells contribute to LDL transport across an endothelial barrier when permeability is increased.