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Abstract
BackgroundAngiogenesis 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.ResultsBy 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.ConclusionsWe 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.
Highlights
Angiogenesis is the process by which new blood vessels arise from pre-existing ones
Fibroblast growth factor-2 (FGF-2)-induced endothelial cell proliferation and survival correlates with increased expression of SRSF1, SRSF3, and SRPK1 proteins In order to identify new molecular mechanisms by which fibroblast growth factors (FGFs)-2 promotes angiogenesis, we used two primary human endothelial cell models, namely human umbilical vein (HUVEC) and human dermal microvascular endothelial cells (HDMEC), grown in standard 2 dimension cell cultures
Using mAb104, a specific antibody targeting phospho-epitope on SR proteins, we further showed an accumulation of P-SRSF3 protein in HDMEC treated with FGF-2 (Fig. 1, c, d)
Summary
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. FGFs act by binding to and activating their cognate tyrosine kinase receptors (fibroblast growth factor receptor, FGFRs), leading to receptor dimerization, trans-phosphorylation, and activation of downstream signaling cascades [2] They exert their angiogenic functions through both paracrine- and autocrine-dependent mechanisms because endothelial cells and other stromal and tumor cells secrete FGFs and/or express FGFRs on their surface [3, 4]. FGF-1/FGF-2 double knockout mice display poor wound healing compared with normal control mice, thereby indicating a pivotal role of FGF/FGFR signaling in tissue repair and neovascularization following injury [13, 14] Overall, these studies highlight a predominant role of FGF-2 during various angiogenic processes. Whether/how FGF-2 regulates post-transcriptional events in endothelial cells to promote angiogenesis remains largely unknown
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