N-VEGF, the forgotten isoform of VEGF-A, activate cellular stress survival circuits

Abstract

AbstractVascular Endothelial Growth Factor A (VEGF-A) is a major angiogenesis stimulator in response to hypoxia. Its first exon possesses an elongated 5’ Untranslated Region (5’UTR) and two Internal Ribosome Entry Sites (IRESs), enabling translation under hypoxia. It also encodes a 180 aa peptide that is in-frame with the coding region of VEGF-A. Upon hypoxia, Long VEGF-A (L-VEGF) is translated from this reading-frame concomitant with canonical VEGF-A isoforms. L-VEGF is proteolytically cleaved upstream to the VEGF-A translation initiation site to generate N-VEGF, which under hypoxia shuttles to cells nuclei. Here we show by RNA-seq that hypoxia-independent nuclear mobilization of N-VEGF into NIH3T3 cells nuclei induced key genes associated with angiogenesis, cellular maintenance, and survival. Conversely, CRISPR-Cas9 mediated deletion of N-VEGF resulted in cells sensitive to hypoxia. Our results highlight the role of N-VEGF, the non-canonical VEGF-A isoform, in perpetuating the initial steps of angiogenesis along with the potentiation of cell survival circuits.