Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation

Abstract

Circulating endothelial progenitor cells (EPCs) are incorporated into foci of neovascularization where they undergo differentiation to mature endothelial cells (ECs). We show here that the enzyme sphingosine kinase-1 (SK-1) regulates the rate and direction of EPC differentiation without effect on the hematopoietic compartment. EPCs have high levels of SK-1 activity, which diminishes with differentiation and is, at least partially, responsible for maintaining their EPC phenotype.EPCs from SK-1 knockout mice form more adherent EC units and acquire a mature EC phenotype more rapidly. Conversely, EPCs from mice overexpressing SK-1 in the EC compartment are retarded in their differentiation. Exogenous regulation of SK-1 levels in normal EPCs, by genetic and pharmacologic means, including the immunomodulating drug FTY720, recapitulates these effects on EC differentiation. SK-1 knockout mice have higher levels of circulating EPCs, an exaggerated response to erythropoietin-induced EPC mobilization, and, in a mouse model of kidney ischemia reperfusion injury, exhibit a recovery similar to that of ischemic mice administered exogenous EPCs. Thus, SK-1 is a critical player in EPC differentiation into EC pointing to the potential utility of SK-1 modifying agents in the specific manipulation of endothelial development and repair. (Blood. 2009;

Tumor Necrosis Factor-Induced Neutrophil Adhesion Occurs Via Sphingosine Kinase-1-Dependent Activation of Endothelial α5β1 Integrin

“…Cells were infected with a dose of virus previously determined to lead to a five-to tenfold increase in SK-1 activity and the same dose of control EV adenovirus was used. 17 …”

“…However, S1P can also act intracellularly, possibly through histone deacetylases 16 or other as yet unknown binding partners, where the ablation of receptor signaling through both chemical or genetic mechanisms does not abrogate S1P effects on cell proliferation, Ca 2ϩ mobilization, EC survival, nor the differentiation of endothelial progenitor cells. 10,17 SK-1 has two functional states, an intrinsic or basal state and an agonist-induced activated state, which requires its phosphorylation and is responsible for its oncogenic properties. 18 More recently we observed that SK-1 activates ␣ v ␤ 3 integrin to mediate EC survival signaling pathway via formation of a heterotrimeric complex between SK-1, ␣ v ␤ 3 and CD31.…”

Attenuation of flightless I improves wound healing and enhances angiogenesis in a murine model of type 1 diabetes

“…HUVEC were seeded on angiogenesis plate (1 μ-Slide Angiogenesis ibiTreat; Ibidi, Munich, Germany) coated with 12 μl of Matrigel (354234, BD Biosciences, Bedford, MA, USA). The number of tubes was counted as previously described [22,27] and data were derived from an average of four donors.…”

Sphingosine Kinase-1 Associates with Integrin αVβ3 to Mediate Endothelial Cell Survival

“…44 Increasing evidence for S1P as a bone fide second messenger 11 includes our own studies showing that S1P receptor inhibitors VPC23019 and JTE-013, although efficient for inhibiting agonist-induced SK-1 activity, 24,45 failed to have any effect on survival in the SK-1-overexpressing EC 24 or on the differentiation of endothelial progenitor cells. 46 Paik et al 47 previously described S1P 1 -and S1P 3 -mediated Rho signaling in ␣ v ␤ 3 activation for EC migration. This current study suggests a mode of action via membrane-localized components that is key to survival signaling pathways.…”