Blood-borne sphingosine 1-phosphate maintains vascular resistance and cardiac function.

Sphingosine 1-phosphate (S1P) circulates in plasma bound to high-density lipoproteins (HDL) and albumin. In mice, isolated deficiency in HDL-S1P and endothelial cell S1P receptor (R)-1 both trigger hypertension, supporting an essential role for HDL-S1P in endothelial function. Physiological roles of albumin-S1P and myocyte S1PRs in the cardiovascular system remain incompletely defined. We report that depletion of all circulating S1P pools induces hypotension and lack of blood pressure increase with age, which contrasts with HDL-S1P deficiency and suggests an essential role for albumin-S1P in cardiovascular homeostasis. Left ventricular contractile function was also reduced but cardiac output preserved in a basal state. Cardiac function and blood pressure was partially or fully normalized by bone marrow transplantation or transfusion of erythrocytes capable of S1P production. Hypotension was accompanied by reduced peripheral resistance, and BSA-S1P, but not S1P complexed to an HDL-like chaperone, dose-dependently increased vascular resistance in isolated perfused kidneys via S1PR2 and S1PR3. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent blood pressure regulation and pointed to a distinct origin of the cardiac phenotype. These observations suggests that albumin-S1P crosses the endothelium in resistance arteries to access contractile receptors, and that myocyte S1PR signaling is essential for vascular resistance and blood pressure maintenance in mice. Overall design: RNA-seq profiling of hearts from plasma S1Pless (Sphk1f/-:2f/-:Mx1Cre+) and littermate control male mice