Angiogenesis is the process by which new blood vessels arise from pre-existing ones. Fibroblast growth factor-2 (FGF-2), a leading member of the FGF family of heparin-binding growth factors, contributes to normal as well as pathological angiogenesis. Pre-mRNA alternative splicing plays a key role in the regulation of cellular and tissular homeostasis and is highly controlled by splicing factors, including SRSFs. SRSFs belong to the SR protein family and are regulated by serine/threonine kinases such as SRPK1. Up to now, the role of SR proteins and their regulators in the biology of endothelial cells remains elusive, in particular upstream signals that control their expression. By combining 2D endothelial cells cultures, 3D collagen sprouting assay, a model of angiogenesis in cellulose sponges in mice and a model of angiogenesis in zebrafish, we collectively show that FGF-2 promotes proliferation, survival, and sprouting of endothelial cells by activating a SRSF1/SRSF3/SRPK1-dependent axis. In vitro, we further demonstrate that this FGF-2-dependent signaling pathway controls VEGFR1 pre-mRNA splicing and leads to the generation of soluble VEGFR1 splice variants, in particular a sVEGFR1-ex12 which retains an alternative last exon, that contribute to FGF-2-mediated angiogenic functions. Finally, we show that sVEGFR1-ex12 mRNA level correlates with that of FGF-2/FGFR1 in squamous lung carcinoma patients and that sVEGFR1-ex12 is a poor prognosis marker in these patients. We demonstrate that FGF-2 promotes angiogenesis by activating a SRSF1/SRSF3/SRPK1 network that regulates VEGFR1 alternative splicing in endothelial cells, a process that could also contribute to lung tumor progression.

中文翻译：

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FGF-2通过控制内皮细胞中VEGFR1剪接的SRSF1/SRSF3/SRPK1依赖轴促进血管生成

血管生成是新血管从先前存在的血管中产生的过程。成纤维细胞生长因子 2 (FGF-2) 是肝素结合生长因子 FGF 家族的主要成员，有助于正常和病理性血管生成。Pre-mRNA 选择性剪接在调节细胞和组织内稳态中起关键作用，并且受剪接因子（包括 SRSF）的高度控制。SRSFs 属于 SR 蛋白家族，受 SRPK1 等丝氨酸/苏氨酸激酶的调控。到目前为止，SR 蛋白及其调节剂在内皮细胞生物学中的作用仍然难以捉摸，特别是控制其表达的上游信号。通过结合 2D 内皮细胞培养物、3D 胶原发芽试验、小鼠纤维素海绵中的血管生成模型和斑马鱼的血管生成模型，我们共同表明，FGF-2 通过激活 SRSF1/SRSF3/SRPK1 依赖性轴促进内皮细胞的增殖、存活和发芽。在体外，我们进一步证明了这种依赖 FGF-2 的信号通路控制 VEGFR1 前 mRNA 剪接并导致产生可溶性 VEGFR1 剪接变体，特别是保留最后一个外显子的 sVEGFR1-ex12，这有助于 FGF- 2介导的血管生成功能。最后，我们发现 sVEGFR1-ex12 mRNA 水平与鳞状肺癌患者的 FGF-2/FGFR1 水平相关，并且 sVEGFR1-ex12 是这些患者预后不良的标志物。我们证明 FGF-2 通过激活调节内皮细胞中 VEGFR1 可变剪接的 SRSF1/SRSF3/SRPK1 网络来促进血管生成，这一过程也可能有助于肺肿瘤的进展。