S1P1 inhibits sprouting angiogenesis during vascular development
S1P1 inhibits sprouting angiogenesis during vascular development
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DOI：
10.1242/dev.078550
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发表时间：
2012-10-15
期刊：
影响因子：
4.6
通讯作者：
Zelzer, Elazar
中科院分区：
文献类型：
--
作者：
Ben Shoham, Adi;Malkinson, Guy;Zelzer, Elazar
血管系统和形成器官之间的协调对于胚胎的正常发育是必不可少的。血管系统通过萌发血管生成来扩张，在此过程中，顶端细胞形成丝状足孔，并入毛细管环。虽然已知有几个分子，如血管内皮生长因子A(VEGFA)，可诱导萌发，但终止这一过程以确保新陈代谢稳定性的机制仍不清楚。鞘氨醇-1-磷酸受体1(S1P(1))在血管成熟过程中介导内皮细胞和壁细胞之间的相互作用。体外研究发现，S1P(1)是一种促血管生成因子。在这里，我们表明，S1P(1)在血管发育过程中作为内皮细胞(EC)自主的负调控因子，对萌发的血管生成起着调节作用。在血管成熟前，在S1P(1)缺失的小鼠胚胎的四肢中发现了严重的血管大小异常和过度发芽，这暗示了S1P(1)作为一种抗血管生成因子的先前未知的、壁细胞无关的作用。当S1P(1)在ECs中的表达被特异性阻断时，观察到类似的表型，表明S1P(1)对萌发的影响是EC自主的。S1P(1)基因敲除斑马鱼胚胎中类似的血管异常表明这一机制的跨物种进化保守。最后，S1P(1)和Vegfa之间的遗传相互作用表明，这些因素相互作用，调节维管发育，因为Vegfa促进萌发，而S1P(1)抑制它，以防止新血管过度萌发和融合。更广泛地说，由于S1P(1)的配体S1P是通过血液传播的，我们的发现表明了一种新的血管生成调节模式，一旦血管床建立并发挥功能，血流就会关闭一个负反馈环路，抑制萌芽的血管生成。
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.