S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity

Signaling through sphingosine-1-phosphate receptor 1 (S1P(1)) promotes blood vessel barrier function. Degradation of S1P(1) results in increased vascular permeability in the lung and may explain side effects associated with administration of FTY720, a functional antagonist of the S1P(1) 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 S1P(1) in blood vessels in the colon has not been investigated. In the present study, we show that S1P(1) is overexpressed in the colonic mucosa of UC patients. This increase in S1P(1) 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 S1P(1) is critical to maintaining colonic vascular integrity and may play a role in UC pathogenesis.-Montrose, D. C., E. J. Scherl, B. P. Bosworth, X. K. Zhou, B. Jung, A. J. Dannenberg, and T. Hla. S1P(1) localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J. Lipid Res. 2013. 54: 843-851.