Lysyl oxidase-like 2 is a regulator of angiogenesis through modulation of endothelial-to-mesenchymal transition

J Cell Physiol. 2019 Jul;234(7):10260-10269. doi: 10.1002/jcp.27695. Epub 2018 Nov 1.

Abstract

Lysyl oxidase-like 2 (LOXL2) belongs to the family of lysyl oxidases, and as such promotes crosslinking of collagens and elastin by oxidative deamination of lysine residues. In endothelial cells (ECs), LOXL2 is involved in crosslinking and scaffolding of collagen IV. Additionally, several reports have shown a role for LOXL2 in other processes, including regulation of gene expression, tumor metastasis, and epithelial-to-mesenchymal transition (EMT). Here, we demonstrate an additional role for LOXL2 in the regulation of angiogenesis by modulation of endothelial-to-mesenchymal transition (EndMT). LOXL2 knockdown in ECs results in decreased migration and sprouting, and concordantly, LOXL2 overexpression leads to an increase in migration and sprouting, independent of its catalytic activity. Furthermore, LOXL2 knockdown resulted in a reduced expression of EndMT markers, and inhibition of transforming growth factor-β (TGF-β)-mediated induction of EndMT. Interestingly, unlike in EMT, overexpression of LOXL2 alone is insufficient to induce EndMT. Further investigation revealed that LOXL2 expression regulates protein kinase B (PKB)/Akt and focal adhesion kinase (FAK) signaling, both pathways that have been implicated in the regulation of EMT. Altogether, our studies reveal a role for LOXL2 in angiogenesis through the modulation of EndMT in ECs, independent of its enzymatic crosslinking activity.

Keywords: angiogenesis; endothelial-to-mesenchymal transition; focal adhesion kinase; lysyl oxidase-like 2; protein kinase B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / genetics
  • Amino Acid Oxidoreductases / metabolism*
  • Cell Movement
  • Cell Proliferation
  • Endothelial Cells / enzymology*
  • Enzyme Activation
  • Epithelial-Mesenchymal Transition*
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Mutation
  • Neovascularization, Physiologic*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction

Substances

  • Amino Acid Oxidoreductases
  • LOXL2 protein, human
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Proto-Oncogene Proteins c-akt