Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

Hypoxia, a major inducer of angiogenesis, triggers major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to bind RNA and to activate FGF1 and VEGFD IRESs in hypoxia while it exhibits an inhibitory effect in normoxia. This suggests a generalized process of IRES-dependent induction of (lymph)angiogenic growth factors in early hypoxia, with a variable IRESome composition. IRES-dependent translation thus appears as a pivotal process to trigger new vessel formation in ischemic heart.