Sphingosine‐1‐phosphate from erythrocytes modulates water and macromolecule permeability in rat microvessels

Abstract

Exogenous sphingosine‐1‐phosphate (S1P) attenuates acute increases in vascular permeability acting through receptor S1P1 to stabilize the endothelial barrier. Recent evidence shows that S1P is synthesized, stored in and released from erythrocytes. This study directly evaluates the contribution of erythrocyte derived S1P to maintain basal permeability to serum albumin in intact individually perfused venular microvessels of rat mesentery. Permeability coefficients (Ps) to albumin, α‐lactalbumin and the hydraulic conductivity (Lp) of mesenteric venules were measured in the presence or absence of perfusates containing rat erythrocytes (RBCs) or RBC conditioned media. Under these conditions RBCs added to the perfusate were the principal source of S1P in the microvessel. Albumin Ps values were stable and within the range expected of blood perfused microvessels (mean 0.5 × 10−6 cm/sec) when RBCs or RBC conditioned media were present. When absent, Ps to albumin or α‐lactalbumin was increased up to 10 fold. The S1P1 receptor antagonist (W146) reversed the stabilizing action of RBCs and Ps increased to the same extent as in the absence of RBCs. W146 also increased Lp in the presence of RBCs used as flow markers. We conclude that erythrocytes are the primary source of S1P that maintains normal venular microvessel permeability. Disease states which reduce RBC derived S1P may increase basal permeability. Supp NIH HL28607