S1P(4) receptor mediates S1P-induced vasoconstriction in normotensive and hypertensive rat lungs

This study aimed to identify receptors mediating sphingosine-1-phosphate (S1P)-induced vasoconstriction in the normotensive and chronic hypoxia-induced hypertensive rat pulmonary circulation. In isolated perfused lungs from normoxic rats, infusion of S1P caused a sustained vasoconstriction, which was not reduced by combinational pretreatment with the dual S1P(1 and 3) receptor antagonist VPC23019 and the S1P(2) receptor antagonist JTE013. The S1P(4) receptor agonists phytosphingosine-1-phospate and VPC23153, but not the dual S1P(1 and 3) receptor agonist VPC24191, caused dose-dependent vasoconstrictions. In hypertensive lungs from chronically hypoxic rats, the vasoconstrictor responses to S1P and VPC23153 were markedly enhanced. The S1P(4) receptor agonist VPC 23153 caused contraction of isolated pulmonary but not of renal or mesenteric arteries from chronically hypoxic rats. S1P(4) receptor protein as well as mRNA were detected in both normotensive and hypertensive pulmonary arteries. In contrast to what has been reported in the systemic circulation and mouse lung, our findings raise the possibility that S1P(4) receptor plays a significant role in S1P-induced vasoconstriction in the normotensive and hypertensive rat pulmonary circulation.