Abstract
S1P-phosphohydrolase 1 (SPP1) putatively antagonizes the prominent effects of sphingosine kinase 1 (Sk1) / sphingosine-1-phosphate (S1P) signalling on microvascular tone. SPP1 mRNA is highly expressed in hamster resistance arteries, and tagged SPP1 protein resides in the cytosol and at the plasma membrane. Overexpression of SPP1 reduced resting tone, Ca2+ sensitivity and myogenic vasoconstriction. Accordingly, treatment with antisense oligonucleotides yielded the opposite results. The co-expression of SPP1 with Sk1 eliminated the previously reported Sk1-mediated enhancements of tone and Ca2+ sensitivity. Co-expression of a phosphatase-dead SPP1 mutant (SPP1H208A) failed to antagonize Sk1, excluding effects of protein overexpression that were unrelated to the S1P-degrading function of SPP1. Treatment with antisense oligonucleotides or the specific inhibitor JTE013 identified (i) the S1P2 receptor as the primary receptor mediating the effects of extracellular S1P, and (ii) the exogenous S1P concentration range where effects are entirely S1P2 mediated. The latter was significantly altered by modulation of SPP1 expression, indicating that SPP1 accesses extracellular S1P pools. We conclude that SPP1 is the primary functional antagonist of Sk1 in the smooth muscle cells of resistance arteries, and consequently possesses potential clinical relevance in the control of tissue perfusion and systemic blood pressure.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
