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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:275.)
© 2007 American Heart Association, Inc.

Vascular Biology

Sphingosine-1-Phosphate Stimulates the Functional Capacity of Progenitor Cells by Activation of the CXCR₄-Dependent Signaling Pathway via the S1P₃ Receptor

Dirk H. Walter; Ulrich Rochwalsky; Johannes Reinhold; Florian Seeger; Alexandra Aicher; Carmen Urbich; Ioakim Spyridopoulos; Jerold Chun; Volker Brinkmann; Petra Keul; Bodo Levkau; Andreas M. Zeiher; Stefanie Dimmeler; Judith Haendeler

From Molecular Cardiology, Department of Internal Medicine III (D.H.W., U.R., J.R., F.S., A.A, C.U., I.S., A.M.Z., S.D., J.H.), University of Frankfurt, Germany; the Department of Molecular Biology (J.C.), Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, Calif; the Institute of Pathophysiology (P.K., B.L.), Center of Internal Medicine, Essen, Germany; and the Novartis Institute for Biomedical Research (V.B.), Basel, Switzerland.

Correspondence to Judith Haendeler, PhD, or Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail j.haendeler{at}em.uni-frankfurt.de or dimmeler@em.uni-frankfurt.de

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.

Treatment of progenitor cells with sphingosine-1-phosphate (S1P), a bioactive lipid, improved blood flow recovery in ischemic hind limbs via the S1P₃ receptor. Mechanistically, S1P induced phosphorylation of the CXCR₄ receptor, the Src kinase, and JAK2. S1P failed to stimulate in vivo blood flow recovery of bone marrow–derived mononuclear cells from CXCR₄^+/– mice. The activation of the CXCR₄ receptor is mediated via the S1P₃ receptor because S1P did not induce Src phosphorylation in progenitor cells from S1P₃^–/– mice.

Key Words: S1P • receptor cross-talk • progenitor cells

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CXCR4, a Key Modulator of Vascular Progenitor Cells

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