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Walter, Dirk H., Rochwalsky, Ulrich, Reinhold, Johannes 
ORCID: https://orcid.org/0000-0003-2412-2574, Seeger, Florian, Aicher, Alexandra, Urbich, Carmen, Spyridopoulos, Ioakim, Chun, Jerold, Brinkmann, Volker, Keul, Petra, Levkau, Bodo, Zeiher, Andreas M., Dimmeler, Stefanie and Haendeler, Judith
(2007)
Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor.
Arteriosclerosis, Thrombosis, and Vascular Biology, 27 (2).
pp. 275-282.
ISSN 1079-5642
Abstract
OBJECTIVE - Sphingosine-1-phosphate (S1P) is a bioactive lipid, which influences migration and proliferation of endothelial cells through activation of S1P receptors and has been shown to support SDF-1 induced migration and bone marrow homing of CD34 progenitors. METHODS AND RESULTS - Here, we show that incubation of patient-derived endothelial progenitor cells (EPCs) with S1P or its synthetic analog FTY720 improved blood flow recovery in ischemic hind limbs. Likewise, recovery of blood flow was dramatically reduced after induction of hindlimb ischemia in mice deficient for the S1P receptor 3 (S1P3). S1P3 bone marrow-derived mononuclear cells (BMCs) failed to augment neovascularization after hind limb ischemia. Of note, treatment of BMCs derived from S1P3 mice with S1P did not rescue blood flow recovery. Mechanistically, S1P and FTY720 induced phosphorylation of CXCR4, activated the Src kinase, and stimulated phosphorylation of JAK2. The contribution of CXCR4 for S1P-mediated effects was further supported by the findings that S1P preincubation failed to stimulate invasion capacity and in vivo blood flow recovery of BMCs from CXCR4 mice. The activation of CXCR4 was dependent on the Src kinase family as demonstrated by preincubation with the Src inhibitor PP2. The activation of the CXCR4 signaling by S1P is mediated via the S1P3 receptor, since S1P-induced Src phosphorylation was abrogated in EPC from S1P3 mice. CONCLUSIONS - S1P agonists might serve as sensitizers of CXCR4-mediated signaling and may be applied in clinical progenitor cell therapy to improve EPC or BMC function in patients with coronary artery disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | progenitor cells,receptor cross-talk,s1p,cardiology and cardiovascular medicine ,/dk/atira/pure/subjectarea/asjc/2700/2705 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 30 Sep 2022 15:31 |
| Last Modified: | 19 Oct 2023 03:26 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/88750 |
| DOI: | 10.1161/01.ATV.0000254669.12675.70 |
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