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Sphingosine-1-Phosphate Receptors Regulate the Transendothelial Transport of HDL and LDL Contrariwise
Jerome Robert, PhD11Group leader, Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland
The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis development. 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 receptors (S1PR) regulate the transendothelial transport of lipoproteins.
Compared to apoE-haploinsufficient mice (CTRL), apoE-haploinsufficient mice with additional endothelium specific knock-in of S1P1 (S1P1-iECKI) or 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, S1P1-iECKI and S1P3-iECKI mice had less atherosclerosis than CTRL mice. In vitro, stimulation with S1PRR agonists increased the transport of HDL but decreased the transport of LDL through human aortic endothelial cells (HAECs). Conversely, inhibition or knock-down of S1P1 or S1P3 decreased the transport of HDL but increased the transport of LDL. Silencing of SCARB1 encoding scavenger receptor B1 (SR-BI) abrogated the stimulation of HDL transport by the S1P3 agonist. The transendothelial transport of 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 LDL transport.
Conclusion: S1P1 and 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.
Speakers
Jérôme Robert