Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells

Vidya Limaye, Pu Xia, Chris Hahn, Malcolm Smith, Mathew A. Vadas, Stuart M. Pitson, Jennifer R. Gamble

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


Sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1- phosphate (S1P), which has potent pro-inflammatory and pro-angiogenic effects. We investigated the effects of raised SK1 levels on endothelial cell function and the possibility that this signaling pathway is activated in rheumatoid arthritis. Human umbilical vein endothelial cells with 3- to 5-fold SK1 (EC SK) overexpression were generated by adenoviral and retroviral-mediated gene delivery. The activation state of these cells and their ability to undergo angiogenesis was determined. S1P was measured in synovial fluid from patients with RA and OA. ECSK showed an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells showed constitutive activation as evidenced by the induction of basal VCAM-1 expression, and further showed a more augmented VCAM-1 and E selectin response to TNF compared with empty vector control cells (ECEV). These changes had functional consequences in terms of enhanced neutrophil binding in the basal and TNF-stimulated states in ECSK. By contrast, over-expression of a dominant-negative SK inhibited the TNF-induced VCAM-1 and E selectin and inhibited PMN adhesion, confirming that the observed effects were specifically mediated by SK. The synovial fluid levels of S1P were significantly higher in patients with RA than in those with OA. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in RA, suggesting that manipulation of SK1 activity in diseases of aberrant inflammation and angiogenesis may be beneficial.

Original languageEnglish
Pages (from-to)424-441
Number of pages18
JournalCellular and Molecular Biology Letters
Issue number3
Publication statusPublished - Sep 2009
Externally publishedYes


  • Angiogenesis
  • Endothelial cells
  • Inflammation
  • Sphingosine kinase
  • TNF


Dive into the research topics of 'Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells'. Together they form a unique fingerprint.

Cite this