Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis

Nan W. Hultgren, Jennifer S. Fang, Mary E. Ziegler, Ricardo N. Ramirez, Duc T. T. Phan, Michaela M. S. Hatch, Katrina M. Welch-Reardon, Antonio E. Paniagua, Lin S. Kim, Nathan N. Shon, David S. Williams, Ali Mortazavi and Christopher C. W. Hughes ()
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Nan W. Hultgren: University of California Irvine
Jennifer S. Fang: University of California Irvine
Mary E. Ziegler: University of California Irvine
Ricardo N. Ramirez: University of California Irvine
Duc T. T. Phan: University of California Irvine
Michaela M. S. Hatch: University of California Irvine
Katrina M. Welch-Reardon: University of California Irvine
Antonio E. Paniagua: University of California, Los Angeles
Lin S. Kim: University of California Irvine
Nathan N. Shon: University of California Irvine
David S. Williams: University of California, Los Angeles
Ali Mortazavi: University of California Irvine
Christopher C. W. Hughes: University of California Irvine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.

Date: 2020
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DOI: 10.1038/s41467-020-18633-z

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