New connections: From understanding to targeting S1P1 on endothelial cells

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Sci. Signal.  15 Aug 2017:
Vol. 10, Issue 492, eaao6115
DOI: 10.1126/scisignal.aao6115

Understanding how the S1P receptor S1P1 is specifically activated in endothelial cells may lead to drugs with fewer side effects.

The lipid mediator sphingosine 1-phosphate (S1P) is ferried in the blood by different chaperone proteins, such as albumin and the lipoprotein ApoM+HDL. Binding of S1P to its receptor S1P1 on endothelial cells stabilizes the developing vascular network, inhibits sprouting angiogenesis, and decreases vascular permeability. A pair of papers from the HLA laboratory reveal that the identity of the S1P chaperone determines the specific signaling pathway triggered by the binding of S1P to S1P1 and provides proof-of-concept evidence that a chaperone that selectively targets S1P to S1P1 on endothelial cells could be used to treat cardiovascular diseases. In the first paper, Galvani et al. found that vascular inflammation and atherosclerosis in mice were suppressed by S1P1 activation. S1P suppressed inflammation in cultured endothelial cells when bound to the lipoprotein ApoM+HDL but not when bound to albumin. Thus, S1P bound to different chaperones triggered distinct or “biased” signaling pathways, which may also contribute to the protective effect of HDL, commonly called “good cholesterol,” in atherosclerosis. However, globally increasing HDL abundance does not suppress endothelial cell inflammation and atherosclerosis, and ApoM is unstable when not bound to HDL. In the second paper, Swendeman et al. generated a stable form of ApoM (ApoM-Fc) that bound to S1P and activated S1P1 in a sustained manner in endothelial cells. Treatment of mice with ApoM-Fc-S1P reduced hypertension induced by angiotensin-II and improved outcomes after experimentally induced myocardial infarction or stroke, without inducing the lymphopenia characteristic of S1P1 agonists. Thus, understanding how signaling pathways operate in a cell- or tissue-specific manner may provide insights into how to design drugs with fewer side effects.

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