LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

C Charles Michel,M Nazeem Nanjee,Waldemar L Olszewski,Norman E Miller

doi:10.1194/jlr.m055053

Abstract

The mechanisms by which LDLs and HDLs cross the vascular endothelium from plasma into interstitial fluid are not understood, and have never been studied in humans in vivo. We determined whether the plasma-to-lymph clearance rates of LDL and HDL conform with those predicted by passive ultrafiltration through intercellular pores, or if it is necessary to invoke an active process such as receptor-mediated transcytosis. Plasma and afferent peripheral lymph were collected under steady-state conditions from 30 healthy men, and assayed for seven globular proteins of molecular radii 2.89-8.95 nm, complement C3, and apo AI, apo AII, and apo B. Plasma-to-lymph clearance rates of the seven proteins fitted the relation expected for molecules of their size when transported through two populations of pores of radius 4.95 and 20.1 nm. The same model parameters were then found to accurately predict the clearance rates of both HDL and LDL. The apparent clearance of complement C3, previously shown to be secreted by cultured endothelium, exceeded that predicted by the model. We conclude that the transport of HDL and LDL from plasma into interstitial fluid across the peripheral vascular endothelium in healthy humans can be explained by ultrafiltration without invoking an additional active process such as transcytosis.

Highlights

The mechanisms by which LDLs and HDLs cross the vascular endothelium from plasma into interstitial fluid are not understood, and have never been studied in humans in vivo
As a positive control, we tested the hypothesis that the apparent clearance rate of complement C3 exceeds that predicted by the model, given that it is known to be secreted by cultured endothelium [26]
We found that the relation of clearance to molecular size, measured as Stokes-Einstein radius, was consistent with a two-pore model of ultrafiltration similar to that described by others [14, 23, 24], in which water and water-soluble molecules are carried through the endothelium by ultrafiltration and diffusion through a large number of small pores in parallel with a much smaller number of larger pores

Summary

Introduction

The mechanisms by which LDLs and HDLs cross the vascular endothelium from plasma into interstitial fluid are not understood, and have never been studied in humans in vivo. We conclude that the transport of HDL and LDL from plasma into interstitial fluid across the peripheral vascular endothelium in healthy humans can be explained by ultrafiltration without invoking an additional active process such as transcytosis.—Michel, C. As proteins of radius у3.2 nm were found to leave entirely in lymph, it is reasonable to assume that this applies to LDL and HDL, given that their radii greatly exceed this figure [10, 11] This interpretation agrees with recent studies of HDL transport via the lymphatic system in mice [12].

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Conclusion