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 #
5R01HL089934-08
Application #
9033136
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2007-07-01
Project End
2016-08-31
Budget Start
2016-04-01
Budget End
2016-08-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
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
Swendeman, Steven L; Xiong, Yuquan; Cantalupo, Anna et al. (2017) An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci Signal 10:
Mendelson, Karen; Pandey, Suveg; Hisano, Yu et al. (2017) The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis. Elife 6:
Mendoza, Alejandra; Fang, Victoria; Chen, Cynthia et al. (2017) Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546:158-161
Yanagida, Keisuke; Liu, Catherine H; Faraco, Giuseppe et al. (2017) Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc Natl Acad Sci U S A 114:4531-4536
Kono, Mari; Conlon, Elizabeth G; Lux, Samantha Y et al. (2017) Bioluminescence imaging of G protein-coupled receptor activation in living mice. Nat Commun 8:1163
Yanagida, Keisuke; Hla, Timothy (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 79:67-91
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
Ding, Bi-Sen; Liu, Catherine H; Sun, Yue et al. (2016) HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. JCI Insight 1:e87058
Gazit, Salomé L; Mariko, Boubacar; Thérond, Patrice et al. (2016) Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock. Circ Res 119:e110-26
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87

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