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Abstract
BackgroundFibroblast growth factor 2 (FGF2) is a major angiogenic factor involved in angiogenesis and arteriogenesis, however the regulation of its expression during these processes is poorly documented. FGF2 mRNA contains an internal ribosome entry site (IRES), a translational regulator expected to allow mRNA expression during cellular stress.Methodology/Principal FindingsIn the present study, we have developed a skin ischemia model in transgenic mice expressing a reporter transgene under the control of the FGF2 IRES. The results reveal that FGF2 is induced at the protein level during ischemia, concomitant with HIF-1α induction and a decrease in FGF2 mRNA. In addition, the FGF2 IRES is strongly activated under these ischemic conditions associated with hypoxia, whereas cap-dependent translation is repressed by 4E-BP hypophosphorylation. We also show that up-regulation of FGF2 protein expression in response to hypoxia correlates with the increase of FGF2 IRES activity in vitro, in human retinoblasts 911. The use of siRNAs targeting HIF or FGF2 indicates that FGF2 and HIF-1α reciprocally regulate their expression/accumulation, by a negative feedback loop in early hypoxia, followed by a positive feedback loop in late hypoxia.Conclusion/SignificanceFGF2 expression is up-regulated in vivo and in vitro in response to hypoxia. Strikingly, this up-regulation is not transcriptional. It seems to occur by an IRES-dependent mechanism, revealing new mechanistic aspects of the hypoxic response. In addition, our data show that FGF2 interacts with HIF-1α in a unique crosstalk, with distinct stages in early and late hypoxia. These data reveal the physiological importance of IRES-dependent translation during hypoxic stress and underline the complexity of the cellular response to hypoxia, suggesting a novel role of FGF2 in the regulation of HIF-1α during the induction of angiogenesis.
Highlights
The establishment of a stable and functional blood vessel network is a complex process requiring several angiogenic factors to stimulate vessel sprouting and remodeling from the primitive vascular network
Fibroblast growth factor 2 (FGF2) protein expression is induced by ischemia We analyzed the levels of FGF2 mRNA and proteins in the proximal part of the ischemic skin flap
These results show that FGF-2 expression is not activated at the transcriptional level in response to ischemia-induced hypoxia and strongly suggests that it could be up-regulated at the translational level
Summary
The establishment of a stable and functional blood vessel network is a complex process requiring several angiogenic factors to stimulate vessel sprouting and remodeling from the primitive vascular network. Fibroblast growth factor 2 (FGF2) is one of the major regulators of blood vessel formation, involved in angiogenesis as well as in arteriogenesis. The response to hypoxic stress generates a transcriptional response mediated by hypoxia-induced factor 1 (HIF-1), whose a subunit is stabilized in the absence of oxygen [2]. PERK activation by hypoxia, mediated by the unfolded protein response, is responsible for translation inhibition by phosphorylating the translation initiation factor eIF2-a [5]. Fibroblast growth factor 2 (FGF2) is a major angiogenic factor involved in angiogenesis and arteriogenesis, the regulation of its expression during these processes is poorly documented. FGF2 mRNA contains an internal ribosome entry site (IRES), a translational regulator expected to allow mRNA expression during cellular stress
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