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Vascular Endothelial S1P2 Receptor Limits Tumor Angiogenesis and Hyperpermeability

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Bioactive Lipid Mediators

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Abstract

The lipid mediator sphingosine-1-phosphate (S1P), which is constitutively produced by sphingosine kinase 1 (SphK1) in circulating erythrocytes and vascular endothelial cells, is exported into plasma to regulate vascular formation, vascular barrier function, vascular tonus, and lymphocyte trafficking through G protein-coupled S1P receptors. S1P1, a principal endothelial S1P receptor, has crucial functions in developmental vascular formation and the maintenance of barrier function. The stabilizing action of S1P1 on endothelial intercellular junctions leads to inhibition of sprouting angiogenesis. S1P1 maintains barrier integrity through the activation of the small G protein Rac. Engagement of S1P1 triggers internalization of S1P1 into early endosomes, in which Rac activation occurs. The class IIα isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is required for the internalization of activated S1P1 and Rac activation on early endosomes. Endothelial cells also express S1P2, which is a prototypic G12/13-coupled chemorepellant receptor to activate RhoA with downstream inhibition of Rac and Akt. Endothelial S1P2, together with S1P2 in myeloid cells, mediates inhibition of tumor angiogenesis. This action, in concert with a direct inhibitory effect of S1P2 on proliferation of tumor cells, suppresses tumor growth. Endothelial S1P2 also suppresses disruption of intercellular junctions and resultant fatal vascular hyperpermeability in anaphylaxis, by limiting mediator-induced activation of eNOS through Rho-Rho kinase-PTEN-dependent suppression of Akt. Thus, endothelial S1P1 and S1P2 have specialized, distinct roles in the regulation of angiogenesis and vascular barrier integrity.

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Abbreviations

S1P:

Sphingosine-1-phosphate

SphK:

Sphingosine kinase

GPCR:

G protein-coupled receptor

PLC:

Phospholipase C

PI3K:

Phosphatidylinositol 3-kinase

PI3K-C2α:

Class IIα isoform of phosphatidylinositol 3-kinase

PAF:

Platelet-activating factor

eNOS:

Endothelial NO synthase

ERK:

Extracellular signal-regulated kinase

JNK:

Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

PTEN:

Phosphatase and Tensin Homolog Deleted from Chromosome 10

HUVECs:

Human umbilical vein endothelial cells

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Japan Society for the Promotion of Science, and grants for Core Research for Evolutional Science and Technology from JST, and IPNU Research Promotion Fund.

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Authors and Affiliations

  1. Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi, Kanazawa, 920-8640, Japan

    Noriko Takuwa M.D., Ph.D., Yasuo Okamoto M.D., Ph.D., Kazuaki Yoshioka Ph.D. & Yoh Takuwa M.D., Ph.D.

  2. Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, 929-1210, Japan

    Noriko Takuwa M.D., Ph.D.

Authors
  1. Noriko Takuwa M.D., Ph.D.
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  2. Yasuo Okamoto M.D., Ph.D.
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  3. Kazuaki Yoshioka Ph.D.
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  4. Yoh Takuwa M.D., Ph.D.
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Correspondence to Yoh Takuwa M.D., Ph.D. .

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  1. Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takehiko Yokomizo

  2. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Makoto Murakami

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Takuwa, N., Okamoto, Y., Yoshioka, K., Takuwa, Y. (2015). Vascular Endothelial S1P2 Receptor Limits Tumor Angiogenesis and Hyperpermeability. In: Yokomizo, T., Murakami, M. (eds) Bioactive Lipid Mediators. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55669-5_17

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