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

Abstract

This article is available online at http://www.jlr.org chylomicrons and VLDLs, are limited in distribution to blood and metabolized at the luminal surface of vascular endothelium by lipoprotein lipase. By contrast, the LDLs and HDLs move between plasma and interstitial fl uid as they transport lipids to and from different cell types. Each LDL particle contains a single molecule of apoB100 (apo B) ( 1, 2 ). The principal protein component of all HDL particles is apo AI, which usually accounts for about 70% of total HDL protein mass. Some HDLs also contain apo AII as the second most abundant protein ( 3 ). Studies of human afferent peripheral lymph have shown that the concentrations of apo AI and apo AII in normal human interstitial fl uid average about one-fi fth of those in plasma ( 4-6 ), while lymph apo B concentration averages only one-tenth ( 4, 7 ). The ratio of HDL to LDL particles in interstitial fl uid has been estimated to average about 50:1 in healthy humans ( 4,8 ).The striking differences in lipoprotein concentrations between plasma and interstitial fl uid, combined with their roles in atherosclerosis, highlight the importance of understanding the mechanisms by which they move into and out of the extravascular compartment. By analyzing data on adipokines of different molecular size, Miller et al. ( 9 ) showed that the principal pathway by which a macromolecule leaves the interstitium of peripheral tissues in humans is determined by its size, the proportion leaving via capillaries decreasing and that via the lymphatic system increasing, as molecular radius rises. As proteins of radius у 3.2 nm were found to leave entirely in lymph, it is reasonable to assume that this applies also to LDL and HDL, given that their radii greatly exceed this fi gure ( 10,11 ). This interpretation agrees with recent studies of HDL transport via the lymphatic system in mice ( 12 ).The mechanisms by which HDL and LDL are transported from plasma into interstitial fl uid are not understood. Two

Lymphatic Vessel Network Structure and Physiology

“…The HDL and LDL of the interstitial fluid and lymph derive from the plasma ultrafiltrate through passive mechanisms (688). However, they also have a distinct composition and physical properties when compared to plasma HDL and LDL (279, 918, 1002).…”

The Lymphatic System: Integral Roles in Immunity

“…Venules, therefore, are unable to absorb the capillary filtrate, so the lymphatic vasculature is required to absorb and return the bulk of this capillary filtrate to the bloodstream. This fluid also passes across the endothelial glycocalyx, a layer of glycoproteins secreted by the endothelium, such that larger macromolecules present in plasma are most restricted in passage owing to their large size and negative charge (12). Proteins initially present in plasma, from albumin to complement and immunoglobulins, are found within interstitial fluid at lower concentrations than in plasma because of this filtration barrier (Figure 1) (12).…”

“…This fluid also passes across the endothelial glycocalyx, a layer of glycoproteins secreted by the endothelium, such that larger macromolecules present in plasma are most restricted in passage owing to their large size and negative charge (12). Proteins initially present in plasma, from albumin to complement and immunoglobulins, are found within interstitial fluid at lower concentrations than in plasma because of this filtration barrier (Figure 1) (12). Adjustments to the filtration barrier are made by vesicular transport (11) or existence and integrity of fenestrae (13), or by any of numerous signals that have been identified to increase intercellular endothelial permeability (14).…”

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis

“…However, it is important to realize that, while our experiments with HDL using the PGA1 tool tracked actual interstitial HDL, our experiments with LDL used adoptive transfer of LDL into skin to illustrate a proof of concept about the potential that molecular size explains our results. However, it may not be the case that endogenous LDL is trapped in the skin of these mice, due to the fact that the larger size of LDL also makes it quite reticent to enter tissues from the blood in the first place (Michel et al, 2015). Indeed, even in healthy tissue, such as healthy arteries, HDL passes through efficiently, but LDL does not disseminate much beyond the intimal endothelium (Nordestgaard et al, 1990).…”