Sphingosine-1-phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that involves in numerous pathophysiological processes. Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair and tumor angiogenesis. The aim of study was to determine the effects of S1P on proliferation and anti-apoptosis of EPCs and their signaling pathways. In this study, we showed that S1P, SEW2871 (a selective S1P receptor 1 (S1PR1) agonist), or CYM5541 (a selective S1P receptor 3 (S1PR3) allosteric agonist promotes the proliferation and attenuates Apoptosis of bone marrow (BM)-derived EPCs. Futhermore, it was showed that S1P could promote EPCs proliferation, which could be significantly inhibited by pretreatment with CAY10444 (an S1PR3 Antagonist), VPC23019 (a selective S1PR(1)/S1PR(3) antagonist), or LY294002 (a PI3K Inhibitor). Moveover, we discovered that S1P could significantly attenuate H₂ O₂ -induced Apoptosis and activation of Caspase-3 in vitro, while W146 (an S1PR1 antagonist), VPC23019, or LY294002 could significantly increase the activation of Caspase-3 and subsequent augmented Apoptosis. Our results indicated that the protective effect of S1P is mediated by activating the PI3K/Akt pathway. In addition, S1P promotion of EPCs proliferation was observed to be mainly mediated through S1PR3 and attenuation of EPCs Apoptosis induced by H₂ O₂ was mainly mediated through S1PR1; both of these effects are mediated by activating the PI3K/Akt pathway, which provides potentially useful therapeutic targets for coronary artery disease, diabetes mellitus, and Cancer treatment.