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

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.

• Authors: David C Montrose, Ellen J Scherl, Brian P Bosworth, Xi Kathy Zhou, Bongnam Jung, Andrew J Dannenberg, Timothy Hla
• Journal: Journal of lipid research (J Lipid Res) Vol. 54 Issue 3 Pg. 843-851 (Mar 2013) ISSN: 1539-7262 [Electronic] United States
• PMID: 23296878 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AUY 954
• Propylene Glycols
• Receptors, Lysosphingolipid
• Thiophenes
• beta-Alanine
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Animals
• Capillary Permeability (drug effects)
• Colitis, Ulcerative (metabolism)
• Colon (drug effects)
• Fingolimod Hydrochloride
• Humans
• Intestinal Mucosa (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Propylene Glycols (pharmacology)
• Real-Time Polymerase Chain Reaction
• Receptors, Lysosphingolipid (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)
• Thiophenes (pharmacology)
• beta-Alanine (analogs & derivatives, pharmacology)