title: 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.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Gaengel
authors.forename: Colin
authors.initials: C
authors.lastname: Niaudet
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hagikura
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Laviña
authors.forename: Bàrbara Laviña
authors.initials: BL
authors.lastname: Siemsen
authors.forename: Lars
authors.initials: L
authors.lastname: Muhl
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hofmann
authors.forename: Lwaki
authors.initials: L
authors.lastname: Ebarasi
authors.forename: Staffan
authors.initials: S
authors.lastname: Nyström
authors.forename: Simin
authors.initials: S
authors.lastname: Rymo
authors.forename: Long Long
authors.initials: LL
authors.lastname: Chen
authors.forename: Mei-Fong
authors.initials: MF
authors.lastname: Pang
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Raschperger
authors.forename: Pernilla
authors.initials: P
authors.lastname: Roswall
authors.forename: Dörte
authors.initials: D
authors.lastname: Schulte
authors.forename: Rui
authors.initials: R
authors.lastname: Benedito
authors.forename: Jimmy
authors.initials: J
authors.lastname: Larsson
authors.forename: Mats
authors.initials: M
authors.lastname: Hellström
authors.forename: Jonas
authors.initials: J
authors.lastname: Fuxe
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.forename: Ralf
authors.initials: R
authors.lastname: Adams
authors.forename: Lars
authors.initials: L
authors.lastname: Jakobsson
authors.forename: Arindam
authors.initials: A
authors.lastname: Majumdar
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Anne
authors.initials: A
authors.lastname: Uv
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D015027:Zebrafish; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C477362:S1PR1 protein, human; C556330:S1pr1 protein, mouse