The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2

Abstract

Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability

“…26,27 Similar embryo lethality around E12.5 was found in S1pr1 or Klf2 knockout mice as a result of severe bleeding throughout the bodies because of defect in maturation of blood vessels, 34,35 suggesting that they both are important in vasculature formation. Klf2 was reported to be a crucial transcription factor to enhance S1pr1 expression in T cells.…”

“…It has been shown that S1P/S1pr1 signaling restricted angiogenic sprouting and stabilized junctional VE-cadherin, which played an important role in the maintenance of vascular integrity and the regulation of vascular permeability. 27 Here, we showed that elevation of miR302-367 expression in ECs upregulated S1pr1, leading to the increased VE-cadherin at endothelial junctions, which restricted retina angiogenesis and improved vascular stability. Either pharmacological or genetic deletion of S1pr1 reversed the upregulation of total and junctional VEcadherin, hence boosted retina angiogenesis and weakened the vascular stability.…”

“…27,33 This study showed elevated miR302-367 expression in EC reduced retinal and embryonic hindbrain sprout angiogenesis, the cells had reduced Erk1/2 but increased Klf2, S1pr1, and VE-cadherin expression. Erk1/2 activated by Vegf could reduce the enhanced expression of Klf2, S1pr1, and VEcadherin, and a specific inhibitor SCH772984 reverse these effects, confirming that Erk1/2-Klf2-S1pr1-VE-cadherin pathway in ECs on elevated expression of miR302-367 contributes to the reduction of sprout angiogenesis.…”

“…It was reported that S1pr1 and its downstream target VE-cadherin restricted sprouting angiogenesis and improve vascular stability. 27 To determine whether upregulation of S1pr1 is responsible for the reduction of retina sprout angiogenesis and improvement of vascular stability on elevated miR302-367 expression, a selective S1pr1 antagonist W146 and genetic S1pr1 deficient S1pr1 fl/fl :miR302-367 ECTg mice were used (Online Figure IB). The results showed that pharmacological blockade of S1pr1 with W146 treatment in miR302-367…”

Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide

“…The mechanism by which ceramide regulates transcription factor HIF-1a requires more investigation. Sphingosine-1-phosphate (S1P), which is a counterpart of ceramide in cell death and proliferation, is well known as a stimulant of angiogenesis [37]. After treatment with dietary Glu-Cer, the serum levels of S1P did not change significantly (data not shown), suggesting that serum S1P may not play a role in angiogenesis in this xenograft model.…”