title: S1P1 inhibits sprouting angiogenesis during vascular development.
abstract: Coordination between the vascular system and forming organs is essential for proper embryonic development. The vasculature expands by sprouting angiogenesis, during which tip cells form filopodia that incorporate into capillary loops. Although several molecules, such as vascular endothelial growth factor A (Vegfa), are known to induce sprouting, the mechanism that terminates this process to ensure neovessel stability is still unknown. Sphingosine-1-phosphate receptor 1 (S1P(1)) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P(1) as a pro-angiogenic factor. Here, we show that S1P(1) acts as an endothelial cell (EC)-autonomous negative regulator of sprouting angiogenesis during vascular development. Severe aberrations in vessel size and excessive sprouting found in limbs of S1P(1)-null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P(1) as an anti-angiogenic factor. A similar phenotype observed when S1P(1) expression was blocked specifically in ECs indicates that the effect of S1P(1) on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p(1) knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P(1) and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P(1) inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P(1), is blood-borne, our findings suggest a new mode of regulation of angiogenesis, whereby blood flow closes a negative feedback loop that inhibits sprouting angiogenesis once the vascular bed is established and functional.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100,  Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Ben Shoham
authors.forename: Guy
authors.initials: G
authors.lastname: Malkinson
authors.forename: Sharon
authors.initials: S
authors.lastname: Krief
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shwartz
authors.forename: Yona
authors.initials: Y
authors.lastname: Ely
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Karina
authors.initials: K
authors.lastname: Yaniv
authors.forename: Elazar
authors.initials: E
authors.lastname: Zelzer
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D049349:Receptors, Lysosphingolipid; D042461:Vascular Endothelial Growth Factor A