title: Angiogenic sprouting is regulated by endothelial cell expression of Slug.
abstract: The Snail family of zinc-finger transcription factors are evolutionarily conserved proteins that control processes requiring cell movement. Specifically, they regulate epithelial-to-mesenchymal transitions (EMT) where an epithelial cell severs intercellular junctions, degrades basement membrane and becomes a migratory, mesenchymal-like cell. Interestingly, Slug expression has been observed in angiogenic endothelial cells (EC) in vivo, suggesting that angiogenic sprouting may share common attributes with EMT. Here, we demonstrate that sprouting EC in vitro express both Slug and Snail, and that siRNA-mediated knockdown of either inhibits sprouting and migration in multiple in vitro angiogenesis assays. We find that expression of MT1-MMP, but not of VE-Cadherin, is regulated by Slug and that loss of sprouting as a consequence of reduced Slug expression can be reversed by lentiviral-mediated re-expression of MT1-MMP. Activity of MMP2 and MMP9 are also affected by Slug expression, likely through MT1-MMP. Importantly, we find enhanced expression of Slug in EC in human colorectal cancer samples compared with normal colon tissue, suggesting a role for Slug in pathological angiogenesis. In summary, these data implicate Slug as an important regulator of sprouting angiogenesis, particularly in pathological settings.
authors.affiliation: The Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Welch-Reardon
authors.forename: Seema M
authors.initials: SM
authors.lastname: Ehsan
authors.forename: Kehui
authors.initials: K
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newman
authors.forename: Monica
authors.initials: M
authors.lastname: Romero-Lopez
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Fong
authors.forename: Steven C
authors.initials: SC
authors.lastname: George
authors.forename: Robert A
authors.initials: RA
authors.lastname: Edwards
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008747:Methylcellulose / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D008747:Methylcellulose; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14
keywords: Angiogenesis; EMT; EndMT; MMP; MT1-MMP; Snai1; Snai2