Abstract
Signaling through sphingosine-1-phosphate receptor₁ (S1P₁) promotes blood vessel barrier function. Degradation of S1P₁ results in increased vascular permeability in the lung and may explain side effects associated with administration of FTY720, a functional antagonist of the S1P₁ receptor that is currently used to treat multiple sclerosis. Ulcerative colitis (UC) is characterized by an increased density of abnormal vessels. The expression or role of S1P₁ in blood vessels in the colon has not been investigated. In the present study, we show that S1P₁ is overexpressed in the colonic mucosa of UC patients. This increase in S1P₁ levels reflects increased vascular density in the inflamed mucosa. Genetic deletion of S1pr1 in mice increases colonic vascular permeability under basal conditions and increases bleeding in experimental colitis. In contrast, neither FTY720 nor AUY954, two S1P receptor-targeting agents, increases bleeding in experimental colitis. Taken together, our findings demonstrate that S1P₁ is critical to maintaining colonic vascular integrity and may play a role in UC pathogenesis.
Highlights
Signaling through sphingosine-1-phosphate receptor1 (S1P1) promotes blood vessel barrier function
The present study shows that S1P1 is strongly expressed in the colonic vasculature in both Ulcerative colitis (UC)
We demonstrate that genetic deletion of S1pr1 results in a vascular defect in the colon under basal conditions and during mucosal injury
Summary
Signaling through sphingosine-1-phosphate receptor1 (S1P1) promotes blood vessel barrier function. Genetic deletion of S1pr1 increased colonic vascular permeability in control mice and colitis-associated bleeding. The nonparametric Wilcoxon rank-sum test was used to examine differences in various end-points, including S1P1 and PECAM1 expression in human biopsies, S1pr1 expression in mouse colons, vascular permeability by the Evans Blue dye assay, maximum DSS-induced weight loss, platelet counts, and the numbers of circulating lymphocytes between FTY720/AUY954-treated versus vehicle-treated mice.
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