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S1P1 Inhibits Sprouting Angiogenesis During Vascular Development

Adi Ben Shoham, Guy Malkinson, Sharon Krief, Yulia Shwartz, Yona Ely, Napoleone Ferrara, Karina Yaniv, Elazar Zelzer

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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 (S1P1) has been shown to mediate interaction between endothelial and mural cells during vascular maturation. In vitro studies have identified S1P1 as a pro-angiogenic factor. Here, we show that S1P1 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 S1P1-null mouse embryos before vessel maturation imply a previously unknown, mural cell-independent role for S1P1 as an anti-angiogenic factor. A similar phenotype observed when S1P1 expression was blocked specifically in ECs indicates that the effect of S1P1 on sprouting is EC-autonomous. Comparable vascular abnormalities in S1p1 knockdown zebrafish embryos suggest cross-species evolutionary conservation of this mechanism. Finally, genetic interaction between S1P1 and Vegfa suggests that these factors interplay to regulate vascular development, as Vegfa promotes sprouting whereas S1P1 inhibits it to prevent excessive sprouting and fusion of neovessels. More broadly, because S1P, the ligand of S1P1, 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.