Beschreibung:
<jats:p>
Sphingosine-1-phosphate (S1P), which mediates pleiotropic actions within the vascular system, is a prominent regulator of microvascular tone. By virtue of its S1P-degrading function, we hypothesized that S1P-phosphohydrolase 1 (SPP1) is an important regulator of tone in resistance arteries. Hamster gracilis muscle resistance arteries express mRNA encoding SPP1. Overexpression of SPP1 (via transfection of a SPP1
<jats:sup>wt</jats:sup>
) reduced resting tone, Ca
<jats:sup>2+</jats:sup>
sensitivity, and myogenic vasoconstriction, whereas reduced SPP1 expression (antisense oligonucleotides) yielded the opposite effects. Expression of a phosphatase-dead mutant of SPP1 (SPP1
<jats:sup>H208A</jats:sup>
) had no effect on any parameter tested, suggesting that catalytic activity of SPP1 is critical. The enhanced myogenic tone that follows overexpression of S1P-generating enzyme sphingosine kinase 1 (Sk1
<jats:sup>wt</jats:sup>
) was functionally antagonized by coexpression with SPP1
<jats:sup>wt</jats:sup>
but not SPP1
<jats:sup>H208A</jats:sup>
. SPP1 modulated vasoconstriction in response to 1 to 100 nmol/L exogenous S1P, a concentration range that was characterized as S1P
<jats:sub>2</jats:sub>
-dependent, based on the effect of S1P
<jats:sub>2</jats:sub>
inhibition by antisense oligonucleotides and 1 μmol/L JTE013. Inhibition of the cystic fibrosis transmembrane regulator (CFTR) (1) restored S1P responses that were attenuated by SPP1
<jats:sup>wt</jats:sup>
overexpression; (2) enhanced myogenic vasoconstriction; but (3) had no effect on noradrenaline responses. We conclude that SPP1 is an endogenous regulator of resistance artery tone that functionally antagonizes the vascular effects of both Sk1
<jats:sup>wt</jats:sup>
and S1P
<jats:sub>2</jats:sub>
receptor activation. SPP1 accesses extracellular S1P pools in a manner dependent on a functional CFTR transport protein. Our study assigns important roles to both SPP1 and CFTR in the physiological regulation of vascular tone, which influences both tissue perfusion and systemic blood pressure.
</jats:p>