Department of Cardiology and Angiology I, University Heart Centre Freiburg - Bad Krozingen, Freiburg, Germany.
PLoS One. 2013 Sep 2;8(9):e70873. doi: 10.1371/journal.pone.0070873. eCollection 2013.
Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.
叉头框（Fox）转录因子是心血管发育的重要调节因子，最近有几项研究表明，几种 Fox 蛋白可调节胚胎和出生后血管生成。然而，FoxP 亚家族的作用尚未得到研究，该亚家族在心血管组织中高度表达。在这里，我们发现转录因子 FoxP1 是内皮细胞中表达最高的 FoxP 蛋白，并且在小鼠后肢缺血时新生血管形成部位上调。FoxP1 的沉默导致培养的内皮细胞增殖、管形成和迁移受到强烈抑制。因此，斑马鱼中 FoxP1 的敲低导致体节间血管形成中断。通过基因表达谱分析，我们发现 FoxP1 诱导内皮细胞转录组的特异性变化，并作为 semaphorin 5B 的抑制剂发挥作用，此前已将其描述为神经元抑制因子。我们的研究结果表明，semaphorin 5B 也作为 FoxP1 依赖性内皮细胞增殖、迁移和出芽的抑制剂发挥作用，介导 FoxP1 的作用。总之，我们的数据表明转录因子 FoxP1 对于内皮细胞的血管生成功能至关重要，并作为抑制性导向线索 semaphorin 5B 的抑制剂发挥作用，这表明 FoxP1 在调节新生血管形成方面具有重要功能。
