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Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate
Pernille M Christensen1, Catherine H Liu2, Steven L Swendeman2
1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Biomedical Sciences University of Copenhagen, Copenhagen, Denmark;
Abstract:
Apolipoprotein M (ApoM) transports sphingosine-1-phosphate (S1P) in plasma, and ApoM-deficient mice (Apom(-/-)) have ∼50% reduced plasma S1P levels. There are 5 known S1P receptors, and S1P induces adherens junction formation between endothelial cells through the S1P1 receptor, which in turn suppresses vascular leak. Increased vascular permeability is a hallmark of inflammation. The purpose of this study was to explore the relationships between vascular leakage in ApoM deficiency and S1P1 function in normal physiology and in inflammation. Vascular permeability in the lungs was assessed by accumulation of dextran molecules (70 kDa) and was increased ∼40% in Apom(-/-) mice compared to WT (C57Bl6/j) mice. Reconstitution of plasma ApoM/S1P or treatment with an S1P1 receptor agonist (SEW2871) rapidly reversed the vascular leakage to a level similar to that in WT mice, suggesting that it is caused by decreased plasma levels of S1P and reduced S1P1 stimulation. In a carrageenan-induced model of inflammation, Apom(-/-) mice had increased vascular leakage compared with that in WT mice. Adenoviral overexpression of ApoM in Apom(-/-) mice decreased the vascular leakage compared to adenoviral overexpression of green fluorescent protein. The study suggests that vascular leakage of albumin-sized particles in ApoM deficiency is S1P- and S1P1-dependent and this dependency exacerbates the response to inflammatory stimuli.-Christensen, P. M., Liu, C. H., Swendeman, S. L., Obinata, H., Qvortrup, K., Nielsen, L B., Hla, T., Di Lorenzo, A., Christoffersen, C. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1.
Insights
Apolipoprotein M deficiency reduces plasma sphingosine-1-phosphate, increasing vascular leakage. Restoring ApoM/S1P or activating S1P1 receptors reverses this, highlighting S1P1
Area of Science:
- Vascular biology
- Lipid metabolism
- Inflammation research
Background:
- Apolipoprotein M (ApoM) is a key transporter of sphingosine-1-phosphate (S1P) in plasma.
- Reduced plasma S1P levels are observed in ApoM-deficient mice (Apom(-/-)).
- S1P signaling through the S1P1 receptor is crucial for maintaining endothelial barrier integrity and suppressing vascular leak.
Purpose of the Study:
- To investigate the link between ApoM deficiency, vascular leakage, and S1P1 receptor function.
- To determine if impaired endothelial barrier function in ApoM deficiency is S1P1-dependent.
- To assess the impact of ApoM deficiency on vascular permeability during inflammation.
Main Methods:
- Assessment of lung vascular permeability using dextran accumulation in ApoM-deficient and wild-type mice.
- Pharmacological intervention with an S1P1 receptor agonist (SEW2871).
- ApoM/S1P reconstitution experiments and adenoviral gene delivery in Apom(-/-) mice.
- Carrageenan-induced inflammation model to evaluate vascular leakage.
Main Results:
- Apom(-/-) mice exhibited approximately 40% increased vascular permeability in the lungs compared to wild-type mice.
- Treatment with SEW2871 or reconstitution of plasma ApoM/S1P rapidly normalized vascular leakage in Apom(-/-) mice.
- ApoM deficiency exacerbated carrageenan-induced vascular leakage, which was attenuated by adenoviral ApoM overexpression.
- Vascular leakage of albumin-sized particles in ApoM deficiency is dependent on S1P and S1P1 signaling.
Conclusions:
- Impaired endothelial barrier function in ApoM deficiency is primarily due to reduced S1P levels and subsequent decreased S1P1 receptor stimulation.
- The S1P-S1P1 pathway is critical for maintaining vascular integrity.
- ApoM deficiency exacerbates inflammatory responses by compromising the endothelial barrier function in an S1P1-dependent manner.
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