Editors' ChoiceAngiogenesis

Sprouting Vessels with Nrf2

Sci. Signal.  15 Oct 2013:
Vol. 6, Issue 297, pp. ec248
DOI: 10.1126/scisignal.2004810

Angiogenesis, the sprouting of new branches from existing blood vessels, is required for development and adult tissue growth and can contribute to disease progression. Angiogenesis involves the formation of morphologically and functionally distinct endothelial cells, including the tip cell, which responds to vascular endothelial growth factor (VEGF) by producing the Notch ligand Delta4, and the stalk cell, which responds to Delta4 with Notch activation leading to inhibition of expression of VEGFR2, encoding the receptor for VEGF. Wei et al. reported that the transcription factor Nrf2 is required for angiogenesis in the developing retina. Mice with global or endothelial cell–specific knockout of Nrf2 had reduced endothelial tip cells, endothelial cell proliferation, vessel branching, and vascular density in the developing retina. Loss of Nrf2 increased Delta4-encoding mRNA and activation of Delta-Notch target genes in whole retinas and in laser-captured, microdissected vessels. Inhibition of Notch signaling with neutralizing antibodies targeting Delta4 or small molecules that inhibit γ-secretase–mediated Notch activation increased vascular density in the retinas of Nrf2-knockout mice. Retinas from mice with endothelial cell–specific knockout of Keap1, a negative regulator of Nrf2, had increased retinal endothelial tip cells, endothelial cell proliferation, vessel branching, and vascular density and decreased abundance of Delta4-encoding mRNA and activation of Delta-Notch target genes. In cultured human retinal endothelial cells (HRECs), knockdown of Keap1 decreased VEGF-induced phosphorylation of VEGFR and its target AKT and decreased expression of Delta4 and Delta-Notch target genes. Knockdown of Keap1 in HRECs also abrogated Notch activation when the cells were grown on plates coated with recombinant Delta4. Thus, these data suggested that Nrf2 activation decreases VEGF-induced Delta4 production by the tip cell and Notch activation in the stalk cell, leading to enhanced sprouting of endothelial branches, and that this pathway may be a target for anti-angiogenic therapy in cancer and other diseases.

Y. Wei, J. Gong, R. K. Thimmulappa, B. Kosmider, S. Biswal, E. J. Duh, Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching. Proc. Natl. Acad. Sci. U.S.A. 110, E3910–E3918 (2013).[Abstract][Full Text]