Sphingosine-1-phosphate receptor 3 regulates the transendothelial transport of high-density lipoproteins and low-density lipoproteins in opposite ways

Cardiovasc Res. 2024 Apr 30;120(5):476-489. doi: 10.1093/cvr/cvad183.

Abstract

Aims: The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis. It is controversial whether this happens by filtration or regulated transendothelial transport.Because sphingosine-1-phosphate (S1P) preserves the endothelial barrier, we investigated in vivo and in vitro, whether S1P and its cognate S1P-receptor 3 (S1P3) regulate the transendothelial transport of lipoproteins.

Methods and results: Compared to apoE-haploinsufficient mice (CTRL), apoE-haploinsufficient mice with additional endothelium-specific knock-in of S1P3 (S1P3-iECKI) showed decreased transport of LDL and Evan's Blue but increased transport of HDL from blood into the peritoneal cave. After 30 weeks of high-fat diet feeding, S1P3-iECKI mice had lower levels of non-HDL-cholesterol and less atherosclerosis than CTRL mice. In vitro stimulation with an S1P3 agonist increased the transport of 125I-HDL but decreased the transport of 125I-LDL through human aortic endothelial cells (HAECs). Conversely, inhibition or knock-down of S1P3 decreased the transport of 125I-HDL but increased the transport of 125I-LDL. Silencing of SCARB1 encoding scavenger receptor B1 (SR-BI) abrogated the stimulation of 125I-HDL transport by the S1P3 agonist. The transendothelial transport of 125I-LDL was decreased by silencing of SCARB1 or ACVLR1 encoding activin-like kinase 1 but not by interference with LDLR. None of the three knock-downs prevented the stimulatory effect of S1P3 inhibition on transendothelial 125I-LDL transport.

Conclusion: S1P3 regulates the transendothelial transport of HDL and LDL oppositely by SR-BI-dependent and SR-BI-independent mechanisms, respectively. This divergence supports a contention that lipoproteins pass the endothelial barrier by specifically regulated mechanisms rather than passive filtration.

Keywords: Endothelium; HDL; LDL; SR-BI; Sphingosine-1-phosphate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Atherosclerosis* / prevention & control
  • Biological Transport
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells* / metabolism
  • Humans
  • Lipoproteins, HDL* / genetics
  • Lipoproteins, HDL* / metabolism
  • Lipoproteins, LDL* / metabolism
  • Lysophospholipids*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Receptors, Lysosphingolipid* / genetics
  • Receptors, Lysosphingolipid* / metabolism
  • Scavenger Receptors, Class B* / genetics
  • Scavenger Receptors, Class B* / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors* / genetics
  • Sphingosine-1-Phosphate Receptors* / metabolism

Substances

  • Sphingosine-1-Phosphate Receptors
  • Scavenger Receptors, Class B
  • Lipoproteins, HDL
  • Scarb1 protein, mouse
  • Lipoproteins, LDL
  • Receptors, Lysosphingolipid
  • S1pr3 protein, mouse
  • SCARB1 protein, human
  • sphingosine-1-phosphate receptor-3, human
  • sphingosine 1-phosphate
  • Sphingosine
  • Lysophospholipids