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

• Published in: Developmental cell 2012-09, Vol.23 (3), p.587-599
• Main Authors: Gaengel, Konstantin, Niaudet, Colin, Hagikura, Kazuhiro, Laviña, Bàrbara, Muhl, Lars, Hofmann, Jennifer J., Ebarasi, Lwaki, Nyström, Staffan, Rymo, Simin, Chen, Long Long, Pang, Mei-Fong, Jin, Yi, Raschperger, Elisabeth, Roswall, Pernilla, Schulte, Dörte, Benedito, Rui, Larsson, Jimmy, Hellström, Mats, Fuxe, Jonas, Uhlén, Per, Adams, Ralf, Jakobsson, Lars, Majumdar, Arindam, Vestweber, Dietmar, Uv, Anne, Betsholtz, Christer
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; beta; Biological and medical sciences; blood; Cadherins - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell receptors; Cell structures and functions; cells; Cells, Cultured; development; Endothelial Cells - metabolism; endothelial growth-factor; Fundamental and applied biological sciences. Psychology; Humans; lymphocyte egress; Medical Biotechnology; Medicin och hälsovetenskap; Medicinsk bioteknologi; Mice; Mice, Knockout; Mice, Transgenic; Miscellaneous; Molecular and cellular biology; Neovascularization, Physiologic; pdgf-b; protein-coupled receptor; Receptors, Lysosphingolipid - deficiency; Receptors, Lysosphingolipid - metabolism; sphingosine 1-phosphate; vascular; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Zebrafish
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2012.08.005

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. ► Sphingosine-1-phosphate receptor-1 (Edg1) is a negative regulator of angiogenesis ► Loss of S1pr1 (Edg1) causes endothelial hyperplasia and derangement of the aorta ► S1PR1 (Edg1) regulates cellular adhesion, motility, and VE-cadherin localization ► S1PR1 (Edg1) regulates VEGF-induced VEGFR2 signaling and internalization Angiogenesis, the formation of new blood vessels from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Gaengel et al. report that sphingosine-1-phosphate receptor 1 (S1PR1 or Edg1) inhibits angiogenesis and promotes acquisition of vascular stability by regulating the interplay between VE-cadherin and VEGFR2.