Sphingosine 1-phosphate-induced vasoconstriction is elevated in mesenteric resistance arteries from aged female rats

1 Sphingosine 1-phosphate (S1P), a bioactive lipid, signals through cell surface receptors to induce vasoconstriction and activate endothelial nitric oxide synthase (eNOS), suggesting a role for S1P in vascular tone modulation. 2 Using a model of aging in female rats, we investigated the vasoactivity of S1P and the roles of eNOS and estrogen replacement in modulation of that vasoactivity. 3 Mesenteric arteries from aged female rats were significantly more sensitive to S1P-induced vasoconstriction than arteries from young female rats, and reached greater maximum constriction (58.2+/-2.98 vs 34.8+/-4.44%; P<0.005). Modulation of this vasoconstriction by pretreating vessels with the NOS inhibitor L-NAME occurred only in young vessels. 4 Ovariectomy reduced the maximum S1P-induced vasoconstriction observed in intact aged rats. Estrogen replacement did not appear to have an independent beneficial effect. However, estrogen replacement did restore nitric oxide modulation of S1P-induced vasoconstriction. 5 Expression of the S1P(1) receptor, through which eNOS can be activated, was reduced in vessels from aged rats. S1P(1) receptor expression was restored in vessels from the estrogen-replaced group. 6 S1P is a novel mediator of vascular tone through induction of both vasoconstriction and vasodilation. Reduced S1P(1) receptor expression on aging vessels may explain reduced eNOS activity, which results in greater sensitivity to S1P-induced vasoconstriction. Estrogen replacement in aging female rats restores both S1P(1) receptor expression and NOS activity, suggesting an important role for estrogen in this novel pathway of vascular tone modulation.