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J. Biol. Chem., Vol. 283, Issue 44, 30363-30375, October 31, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/44/30363    most recent M804392200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Estrada, R. Articles by Lee, M.-J. Search for Related Content PubMed PubMed Citation Articles by Estrada, R. Articles by Lee, M.-J. Social Bookmarking                      What's this?

Up-regulating Sphingosine 1-Phosphate Receptor-2 Signaling Impairs Chemotactic, Wound-healing, and Morphogenetic Responses in Senescent Endothelial Cells^*

Rosendo Estrada, Qun Zeng, Hongwei Lu, Harshini Sarojini, Jen-Fu Lee, Steven P. Mathis, Teresa Sanchez^¶, Eugenia Wang, Christopher D. Kontos^||, Chen-Yong Lin^**, Timothy Hla^¶, Bodduluri Haribabu, and Menq-Jer Lee¹

From the Gheens Center on Aging, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, the Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, the ^¶Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, the ^||Department of Medicine, Division of Cardiology, and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, and the ^**Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Vascular endothelial cells (ECs) have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest state called "cellular senescence." It has been shown that sphingolipids may be involved in senescence; however, the molecular links involved are poorly understood. In this study, we investigated the signaling and functions of sphingosine 1-phosphate (S1P), a serum-borne bioactive sphingolipid, in ECs of different in vitro ages. We observed that S1P-regulated responses are significantly inhibited and the S1P_1-3 receptor subtypes are markedly increased in senescent ECs. Increased expression of S1P₁ and S1P₂ was also observed in the lesion regions of atherosclerotic endothelium, where senescent ECs have been identified in vivo. S1P-induced Akt and ERK1/2 activation were comparable between ECs of different in vitro ages; however, PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity was significantly elevated and Rac activation was inhibited in senescent ECs. Rac activation and senescent-associated impairments were restored in senescent ECs by the expression of dominant-negative PTEN and by knocking down S1P₂ receptors. Furthermore, the senescent-associated impairments were induced in young ECs by the expression of S1P₂ to a level similar to that of in vitro senescence. These results indicate that the impairment of function in senescent ECs in culture is mediated by an increase in S1P signaling through S1P₂-mediated activation of the lipid phosphatase PTEN.

Received for publication, June 6, 2008 , and in revised form, August 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01HL071071 (to M. L). This work was also supported by American Heart Association Grant-in-Aid 0755245B (to M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solelyto indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: University of Louisville Health Sciences Center, 580 S. Preston St., Louisville, KY 40202. Tel.: 502-852-7729; Fax: 502-852-2660; E-mail: menqjer.lee{at}louisville.edu.

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