Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein

Abstract

Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P 1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P 1 ) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P 1 ) endothelium-specific knockin of S1P 1 . The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125 I-HDL by human aortic endothelial cells was increased by an S1P 1 agonist but decreased by an S1P 1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125 I-HDL transport by the S1P 1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P 1 , apoE-haploinsufficient mice with endothelium-specific knockin of S1P 1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P 1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.

HDL Composition, Heart Failure, and Its Comorbidities

“…This signaling promotes diverse physiological responses including maintenance of endothelial barrier integrity, promotion of cell survival, and anti-inflammatory effects. Modified from ( 240 – 242 ).…”

Distinct GEFs Couple S1PR1 to Rac for Endothelial Barrier Enhancement and Lymphocyte Trafficking

“…13 An essential role for DOCK4 downstream of S1PR1 in endothelial barrier enhancement raises the question of whether it is also implicated in other endothelial functions regulated by S1PR1 signaling, such as NO synthase activation, suppression of inflammation, and a recently identified role in HDL (high-density lipoprotein) transcytosis. [14][15][16] The bulk of S1P in the blood circulation associates with HDL through high-affinity binding to ApoM (apolipoprotein M). 15 The binding of HDL to SR-B1 (scavenger receptor class B type 1) may present S1P to S1PR1 (Figure ), 15 and S1PR1 activation was recently shown to promote the translocation of SR-B1 to the plasma membrane and the selective transendothelial transport of HDL.…”

“…15 The binding of HDL to SR-B1 (scavenger receptor class B type 1) may present S1P to S1PR1 (Figure ), 15 and S1PR1 activation was recently shown to promote the translocation of SR-B1 to the plasma membrane and the selective transendothelial transport of HDL. 16 Intriguingly, DOCK4 was recently attributed a critical role in the selective endothelial transcytosis of LDL (low-density lipoprotein)…”

“…15 The binding of HDL to SR-B1 (scavenger receptor class B type 1) may present S1P to S1PR1 (Figure), 15 and S1PR1 activation was recently shown to promote the translocation of SR-B1 to the plasma membrane and the selective transendothelial transport of HDL. 16 Intriguingly, DOCK4 was recently attributed a critical role in the selective endothelial transcytosis of LDL (low-density lipoprotein) in atherosclerosis-prone vessels by coupling SR-B1 to Rac1. 17 How SR-B1, S1PR1, and DOCK4 coordinate to specify HDL- versus LDL-selective transendothelial transport remains to be clarified.…”

Engineered high-density lipoprotein particles that chaperone bioactive lipid mediators to combat endothelial dysfunction and thromboinflammation

“…This signaling axis suppresses lymphopoiesis in the bone marrow (22), endothelial injury in the lung (23) liver fibrosis and promotes hepatocyte regeneration (24). In addition, S1PR1 signaling enables trans-endothelial passage of HDL particles into tissue parenchymal spaces (25). These and other studies suggest that HDL-bound S1P activation of endothelial S1PR1 may be therapeutically tractable to suppress endothelial dysfunction.…”