Endothelial pyruvate kinase M2 maintains vascular integrity

J Clin Invest. 2018 Oct 1;128(10):4543-4556. doi: 10.1172/JCI120912. Epub 2018 Sep 17.


The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

Keywords: Metabolism; Vascular Biology; endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism
  • Angiopoietins / genetics
  • Angiopoietins / metabolism
  • Animals
  • Capillary Permeability*
  • Cell Proliferation*
  • Endothelial Cells / cytology
  • Endothelial Cells / enzymology*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism*


  • ANGPT2 protein, human
  • Angiopoietin-2
  • Angiopoietins
  • NF-kappa B
  • angiopoietin 4
  • Pkm protein, mouse
  • Pyruvate Kinase