The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1‐phosphate receptor 1

Schmid, Gerald; Guba, Markus; Ischenko, Ivan; Papyan, A.; Joka, Mareile; Schrepfer, Sabine; Bruns, Christiane; Jauch, Karl‐Walter; Heeschen, Christopher; Graeb, Christian

doi:10.1002/jcb.21181

Cited by 65 publications

(46 citation statements)

References 45 publications

(70 reference statements)

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“…Previous studies identify S1P as a pro-angiogenic factor (Schmid et al, 2007;Yonesu et al, 2009). By contrast, we show that S1P 1 acts to block sprouting and restrict angiogenesis.…”

Section: Research Articlecontrasting

confidence: 58%

S1P1 inhibits sprouting angiogenesis during vascular development

et al. 2012

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SUMMARYCoordination 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.

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“…Previous studies identify S1P as a pro-angiogenic factor (Schmid et al, 2007;Yonesu et al, 2009). By contrast, we show that S1P 1 acts to block sprouting and restrict angiogenesis.…”

Section: Research Articlecontrasting

confidence: 58%

S1P1 inhibits sprouting angiogenesis during vascular development

et al. 2012

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“…3,27 In contrast, other studies have reported that FTY720 actually inhibits vascular endothelial growth factor-induced vascular permeability and angiogenesis. [28][29][30] The antiangiogenic effects of FTY720, though surprising based on its potent agonist activity, are proposed to occur as a result of functional antagonism. Although both S1P and FTY720 have been shown to internalize the S1P 1 receptor into the endosomal pathway, FTY720 induces ubiquitinylation and proteosomal degradation of the receptor.…”

mentioning

confidence: 99%

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Sefcik

Aronin

Awojoodu

et al. 2011

Tissue Engineering Part A

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Proper spatial and temporal regulation of microvascular remodeling is critical to the formation of functional vascular networks, spanning the various arterial, venous, capillary, and collateral vessel systems. Recently, our group has demonstrated that sustained release of sphingosine 1-phosphate (S1P) from biodegradable polymers promotes microvascular network growth and arteriolar expansion. In this study, we employed S1P receptorspecific compounds to activate and antagonize different combinations of S1P receptors to elucidate those receptors most critical for promotion of pharmacologically induced microvascular network growth. We show that S1P 1 and S1P 3 receptors act synergistically to enhance functional network formation via increased functional length density, arteriolar diameter expansion, and increased vascular branching in the dorsal skinfold window chamber model. FTY720, a potent activator of S1P 1 and S1P 3 , promoted a 107% and 153% increase in length density 3 and 7 days after implantation, respectively. It also increased arteriolar diameters by 60% and 85% 3 and 7 days after implantation. FTY720-stimulated branching in venules significantly more than unloaded poly(D, L-lactic-co-glycolic acid). When implanted on the mouse spinotrapezius muscle, FTY720 stimulated an arteriogenic response characterized by increased tortuosity and collateralization of branching microvascular networks. Our results demonstrate the effectiveness of S1P 1 and S1P 3 receptor-selective agonists (such as FTY720) in promoting microvascular growth for tissue engineering applications.

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“…These tubules were visualised by immunostaining for MCAM, which is specifically expressed by ECs (Fig. 1B) (Schmid et al, 2007). Initially, only fibroblasts and human coronary artery ECs (no SMCs) were seeded, which similarly results in the formation of endothelial tubules.…”

Section: S1p Inhibition Of Angiogenesis In a Co-culture Model Requirementioning

confidence: 98%

Sphingosine 1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis.

Mascall

Small

Gibson

et al. 2012

Journal of Cell Science

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SummaryFollowing myocardial infarction, angiogenesis occurs as a result of thrombus formation, which permits reperfusion of damaged myocardium. Sphingosine 1-phosphate (S1P) is a naturally occurring lipid mediator released from platelets and is found in high concentrations at sites of thrombosis. S1P might therefore be involved in regulating angiogenesis following myocardial infarction and might influence reperfusion. The aims of this study were to determine the effects of S1P in human coronary arterial cell angiogenesis and delineate the subsequent mechanisms. An in vitro model of angiogenesis was developed using a co-culture of human coronary artery endothelial cells, human coronary smooth muscle cells and human fibroblasts. In this model, S1P inhibited angiogenesis and this was dependent on the presence of smooth muscle cells. The mechanism of the inhibitory effect was through S1P-induced release of a soluble mediator from smooth muscle cells. This mediator was identified as tissue inhibitor of metalloproteinase-2 (TIMP-2). Release of TIMP-2 was dependent on S1P-induced activation of Rho kinase and directly contributed to incomplete formation of endothelial cell adherens junctions. This was observed as a diffuse localisation of VE-cadherin, leading to decreased tubulogenesis. A similar inhibitory response to S1P was demonstrated in an ex vivo human arterial model of angiogenesis. In summary, S1P-induced inhibition of angiogenesis in human artery endothelial cells is mediated by TIMP-2 from vascular smooth muscle cells. This reduces the integrity of intercellular junctions between nascent endothelial cells. S1P might therefore inhibit the angiogenic response following myocardial infarction.

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The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1‐phosphate receptor 1

Cited by 65 publications

References 45 publications

S1P1 inhibits sprouting angiogenesis during vascular development

S1P1 inhibits sprouting angiogenesis during vascular development

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Sphingosine 1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis.

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