4.6 Article

N-VEGF, the Autoregulatory Arm of VEGF-A

期刊

CELLS
卷 11, 期 8, 页码 -

出版社

MDPI
DOI: 10.3390/cells11081289

关键词

VEGF-A; angiogenesis; hypoxia

资金

  1. Gellman-Lasser Fund for Medical & Biomedical Research and innovation [907679]

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The study reveals the crucial role of N-VEGF as an autoregulatory arm of VEGF-A in angiogenesis and cell survival under hypoxic conditions.
Vascular endothelial growth factor A (VEGF-A) is a secreted protein that stimulates angiogenesis in response to hypoxia. Under hypoxic conditions, a non-canonical long isoform called L-VEGF is concomitantly expressed with VEGF-A. Once translated, L-VEGF is proteolytically cleaved to generate N-VEGF and VEGF-A. Interestingly, while VEGF-A is secreted and affects the surrounding cells, N-VEGF is mobilized to the nucleus. This suggests that N-VEGF participates in transcriptional response to hypoxia. In this study, we performed a series of complementary experiments to examine the functional role of N-VEGF. Strikingly, we found that the mere expression of N-VEGF followed by its hypoxia-independent mobilization to the nucleus was sufficient to induce key genes associated with angiogenesis, such as Hif1 alpha, VEGF-A isoforms, as well as genes associated with cell survival under hypoxia. Complementarily, when N-VEGF was genetically depleted, key hypoxia-induced genes were downregulated and cells were significantly susceptible to hypoxia-mediated apoptosis. This is the first report of N-VEGF serving as an autoregulatory arm of VEGF-A. Further experiments will be needed to determine the role of N-VEGF in cancer and embryogenesis.

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