FGF-2 promotes angiogenesis through a SRSF1/SRSF3/SRPK1-dependent axis that controls VEGFR1 splicing in endothelial cells.
FGF-2 promotes angiogenesis through a SRSF1/SRSF3/SRPK1-dependent axis that controls VEGFR1 splicing in endothelial cells.
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DOI：
10.1186/s12915-021-01103-3
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发表时间：
2021-08-25
期刊：
影响因子：
5.4
通讯作者：
Eymin B
中科院分区：
文献类型：
--
作者：
Jia T;Jacquet T;Dalonneau F;Coudert P;Vaganay E;Exbrayat-Héritier C;Vollaire J;Josserand V;Ruggiero F;Coll JL;Eymin B
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，参与正常和病理性血管生成。前体mRNA选择性剪接在调节细胞和组织内稳态中起关键作用，并且高度受剪接因子（包括SRSFs）控制。SRSFs属于SR蛋白家族，受丝氨酸/苏氨酸激酶如SRPK 1调节。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，3D胶原发芽试验，小鼠纤维素海绵血管生成模型和斑马鱼血管生成模型，我们共同表明FGF-2通过激活SRSF 1/SRSF 3/SRPK 1依赖轴促进内皮细胞增殖，存活和发芽。在体外，我们进一步证明，这种FGF-2依赖性信号通路控制VEGFR 1前mRNA剪接，并导致产生可溶性VEGFR 1剪接变体，特别是sVEGFR 1-ex 12，它保留了一个替代的最后一个外显子，有助于FGF-2介导的血管生成功能。最后，我们发现sVEGFR 1-ex 12 mRNA水平与肺鳞癌患者中FGF-2/FGFR 1相关，并且sVEGFR 1-ex 12是这些患者的不良预后标志物。我们证明FGF-2通过激活SRSF 1/SRSF 3/SRPK 1网络促进血管生成，该网络调节内皮细胞中VEGFR 1的选择性剪接，这一过程也可能有助于肺肿瘤的进展。在线版本包含补充材料，可通过10.1186/s12915-021-01103-3获得。
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. The online version contains supplementary material available at 10.1186/s12915-021-01103-3.
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