A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis

Z. Wang, M. Perez, S. Caja, G. Melino, T. S. Johnson, K. Lindfors, M. Griffin

Research output: Contribution to journalArticlepeer-review


The importance of tissue transglutaminase (TG2) in angiogenesis is unclear and contradictory. Here we show that inhibition of extracellular TG2 protein crosslinking or downregulation of TG2 expression leads to inhibition of angiogenesis in cell culture, the aorta ring assay and in vivo models. In a human umbilical vein endothelial cell (HUVEC) co-culture model, inhibition of extracellular TG2 activity can halt the progression of angiogenesis, even when introduced after tubule formation has commenced and after addition of excess vascular endothelial growth factor (VEGF). In both cases, this leads to a significant reduction in tubule branching. Knockdown of TG2 by short hairpin (shRNA) results in inhibition of HUVEC migration and tubule formation, which can be restored by add back of wt TG2, but not by the transamidation-defective but GTP-binding mutant W241A. TG2 inhibition results in inhibition of fibronectin deposition in HUVEC monocultures with a parallel reduction in matrix-bound VEGFA, leading to a reduction in phosphorylated VEGF receptor 2 (VEGFR2) at Tyr1214 and its downstream effectors Akt and ERK1/2, and importantly its association with b1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity.

Original languageEnglish
Article numbere808
JournalCell Death and Disease
Issue number9
Publication statusPublished - Sep 2013


  • Angiogenesis
  • Crosslinking
  • Tissue transglutaminase
  • Tubule and VEGF

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis'. Together they form a unique fingerprint.

Cite this