Sphingosine 1-phosphate (S1P) signals via its cell-surface G protein-coupled receptors to regulate vascular permeability, inflammation, angiogenesis and vascular maturation. In the past funding period, we found that apolipoprotein M (ApoM) is required for S1P to be associated with HDL and that ApoM+HDL activates the endothelial S1P1 receptor to induce vascular homeostasis and inhibit inflammatory responses. Recent findings also revealed a novel function of ApoM+HDL in the suppression of lymphopoiesis. In addition, we uncovered that the S1P1 receptor is a critical proximal component of shear stress sensing in the vascular endothelium and regulates vascular development and homeostasis. This renewal application aims to further elucidate this fundamental signaling system vascular and immune systems. Since S1P receptor modulators are now used in the clinic to treat autoimmune conditions, it is important to fully define this signaling system and to understand the cardiovascular implications. The overarching hypothesis of this proposal is that an HDL-bound ApoM/ S1P complex in plasma activates S1P receptors to regulate physiologic vascular development and homeostasis as well as immune homeostasis. The balanced activation of multiple S1P receptors by HDL/S1P plays a critical role in normal health of the vascular system and if dysregulated, leads to vascular disease. We propose to elucidate the mechanisms by which ApoM+HDL delivers S1P to its receptors on endothelial cells and regulates biological effects. Second, the physiological importance of ApoM+HDL to regulate vascular inflammation via S1P receptors will be examined in mouse and fish models. Biochemical analysis in cultured endothelial cells, genetic loss-of-function studies in zebrafish and genetic mouse models of receptor function will be conducted to further define the key S1P pathway components. Third, we will explore the novel finding that ApoM+HDL signaling via S1P receptors restrain lymphopoiesis. The concept that ApoM+HDL/S1P regulates immune ontogeny while albumin/S1P mediates immune cell trafficking will be tested rigorously. Therapeutic opportunities with reconstituted ApoM+HDL will be explored. Since S1P receptor modulators have entered the therapeutic era, the findings from this project are likely to have rapid translational potential.

Public Health Relevance

Cardiovascular disease causes major mortality and morbidity in developed and newly developing nations. Injury of endothelial cells of blood vessels is a major cause of the development of heart disease by causing fatty lesions in arteries called atherosclerotic plaques. In this proposal, we will examine the hypothesis that a lipid mediator called sphingosine 1-phosphate (S1P) acts on its receptors on endothelial cells to protect the endothelial cells and thereby retard the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL089934-06A1
Application #
8689590
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2007-07-01
Project End
2018-03-31
Budget Start
2014-04-04
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$423,750
Indirect Cost
$173,750
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Christensen, Pernille M; Liu, Catherine H; Swendeman, Steven L et al. (2016) Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J 30:2351-9
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6
Mendelson, Karen; Lan, Yahui; Hla, Timothy et al. (2015) Maternal or zygotic sphingosine kinase is required to regulate zebrafish cardiogenesis. Dev Dyn 244:948-54
Cantalupo, Anna; Zhang, Yi; Kothiya, Milankumar et al. (2015) Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med 21:1028-37
Galvani, Sylvain; Sanson, Marie; Blaho, Victoria A et al. (2015) HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal 8:ra79
Xiong, Yuquan; Yang, Peiying; Proia, Richard L et al. (2014) Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. J Clin Invest 124:4823-8
Blaho, Victoria A; Hla, Timothy (2014) An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res 55:1596-608
Obinata, Hideru; Gutkind, Sarah; Stitham, Jeremiah et al. (2014) Individual variation of human S1P₁ coding sequence leads to heterogeneity in receptor function and drug interactions. J Lipid Res 55:2665-75
Xiong, Yuquan; Hla, Timothy (2014) S1P control of endothelial integrity. Curr Top Microbiol Immunol 378:85-105

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