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Background 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. Results 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. Conclusions 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. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-021-01103-3.

Additional File 2: Figure S2. Schematic representation of VEGFR1 and VEGFR1 splice variants. sVEGFR1-ex15a results from activation of a cryptic 3’-splice acceptor site upon the use of an alternative polyadenylation site in the latter half of intron 14. sVEGFR1-i13 short and sVEGFR1-i13 long result from alternative polyadenylation at different sites in intron 13 to yield mRNAs encoding the same 867 amino acid sVEGFR1 protein isoform, but with either a 17 or 4146 nt 3’-UTR region. sVEGFR1-ex12 retains an alternative last exon (exon 12). The location of forward and reverse primers used in RT-PCR analyses are indicated as black arrows on each transcript. siRNA sequences target exon 12 for sVEGFR1-ex12 and the junction between exon 13 and retained intron 13 for sVEGFR1-i13. (PPTX 68 kb)

Additional File 1: Figure S1. Effects of FGFR (AZD4547) and SRPK1 (SRPIN340, SPHINX31) inhibitors on VEGF165b protein and total VEGF-A, VEGF121, VEGF165 and VEGF189 mRNA levels in endothelial cells treated or not with FGF-2. (a) Representative VEGF165b immunoblots in HUVEC and HDMEC treated or not (NT) for 72 hours with 3nM FGF-2 in the presence or absence of 10nM AZD4547 (FGFRinh), 10μM SRPIN340 or 5μM SPHINX31 as indicated. GAPDH was used as a loading control. Representative immunoblots of two (HUVEC) and three (HDMEC) independent experiments are presented. (b) HDMEC cells were treated (FGF) or not (NT) with 3nM FGF-2 for 72 hours in the presence or absence of 5μM SPHINX31 (SPH31) or 10μM SRPIN340 as indicated. Graphs represent mean values ± SD of normalized expression of each transcript according to GAPDH mRNA level in 3 independent experiments. For each transcript, the fold change was calculated with value 1 assigned to the normalized expression value obtained in the non treated (control) condition. Unpaired t test, *p

Extracellular matrix (ECM) proteins are major components of most tissues and organs. In addition to their crucial role in tissue cohesion and biomechanics, they chiefly regulate various important biological processes during embryonic development, tissue homeostasis and repair. In essence, ECM proteins were defined as secreted proteins that localized in the extracellular space. The characterization of the human and mouse matrisomes provided the first definition of ECM actors by comprehensively listing ECM proteins and classified them into categories. Because zebrafish is becoming a popular model to study ECM biology, we sought to characterize the zebrafish matrisome using an in-silico gene-orthology-based approach. We report the identification of 1002 genes encoding the in-silico zebrafish matrisome. Using independent validations, we provide evidence for the robustness of the orthology-based approach. Moreover, we evaluated the orthology relationships between human and zebrafish genes at the whole-genome and matrisome levels and showed that the different categories of ECM genes are differentially subjected to evolutionary pressure. Last, we illustrate how the zebrafish matrisome list can be employed to annotate big data using the example of a previously published proteomic study of the skeletal ECM. The establishment of the zebrafish matrisome will undoubtedly facilitate the analysis of ECM components in "-omic" data sets.