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 journalArticle

Abstract

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
Number of pages13
JournalCell Death and Disease
Volume4
Issue number9
Early online date19 Sep 2013
DOIs
Publication statusPublished - 2013

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Human Umbilical Vein Endothelial Cells
Vascular Endothelial Growth Factor A
Cell Culture Techniques
Vascular Endothelial Growth Factor Receptor-2
Coculture Techniques
Guanosine Triphosphate
Fibronectins
Integrins
Small Interfering RNA
Cell Movement
Aorta
Down-Regulation
transglutaminase 2
Proteins

Bibliographical note

Creative Commons attribution-non commercial-share alike unported licence - under this type of licence, readers are free to share (copy, distribute and transmit) and remix (adapt) the contribution under these conditions: attribution in the manner specified by the author or licenser; non-commercial —readers and users cannot re-use the material for commercial purposes; and share alike — if readers or other users alter, transform or build upon the work, they may distribute this work only under the same or similar licence to this one.

Keywords

  • angiogenesis
  • crosslinking
  • tissue transglutaminase
  • tubule and VEGF

Cite this

Wang, Z. ; Perez, M. ; Caja, S. ; Melino, G. ; Johnson, T.S. ; Lindfors, K. ; Griffin, M. / A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis. In: Cell Death and Disease. 2013 ; Vol. 4, No. 9.
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A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis. / Wang, Z.; Perez, M.; Caja, S.; Melino, G.; Johnson, T.S.; Lindfors, K.; Griffin, M.

In: Cell Death and Disease, Vol. 4, No. 9, e808, 2013.

Research output: Contribution to journalArticle

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