FGF-2 promotes angiogenesis through a SRSF1/SRSF3/SRPK1-dependent axis that controls VEGFR1 splicing in endothelial cells

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.

Dual physical dynamic bond-based injectable and biodegradable hydrogel for tissue regeneration

Heparin-binding growth factors are incorporated in a new shear thinning hydrogel for sustained release with prolonged bioactivity for tissue regeneration.

Assessment of heparanase and heparin-binding growth and angiogenesis factors in the uterine cavity fluid in women with impaired reproduction

Introduction. Numerous reports lead to conclusion that either the absence or insufficient amounts of heparanase and heparin binding growth factors on the luminal surface of the epithelium in the endometrium may be associated with impaired reproduction. The aim of this study was to assess the suitability of the fluid from the uterus to predict reproductive disorders. Material and methods. The group consisted of 32 women with 2 or more consecutive unexplained miscarriages, and 33 idiopathic infertility patients; the control group comprised 22 women with normal reproductive potential. Concentration of the studied factors was assayed by ELISA in uterine fluid.Results. The uterine flushings from women with two or more consecutive miscarriages showed significantly lower concentrations of HPA1 (p < 0.001) compared to the control group and infertile patients. In contrast, we didn't observe statistically significant differences of concentration of HB-EGF, VEGF, FGF2 in the studied groups. Statistically significant correlations were obtained between the levels of HPA1 and growth factors in all groups p < 0.05. The ROC curve was used to test the diagnostic value of HPA1. With a cut-off point of 8.56 U/L for HPA1 levels, we achieved 58.6% sensitivity and 84.6% specificity in the detection of women with recurrent miscarriage compared to fertile controls and infertile women combined. The area under curve (AUC) value was 0.751. Conclusions. The procedure for determining the concentrations of HPA1, HB-EGF, VEGF, FGF2 by ELISA in fluids derived from the uterine cavity is insufficient to predict either success of reproduction or reproductive disorders.