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 β1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity.

Wang, Z., Perez, M., Caja, S., Melino, G., Johnson, T., Lindfors, K., et al. (2013). A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis. CELL DEATH & DISEASE, 4, e808-e808 [10.1038/cddis.2013.318].

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

MELINO, GENNARO;
2013-01-01

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 β1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity.
2013
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Vascular Endothelial Growth Factor A; Cell Movement; Animals; Extracellular Space; Humans; HEK293 Cells; Chick Embryo; Transglutaminases; Disease Models, Animal; Mice; Human Umbilical Vein Endothelial Cells; Enzyme Inhibitors; GTP-Binding Proteins; Cell Shape; Rats; Gene Knockdown Techniques; Cross-Linking Reagents; Extracellular Matrix; Fibronectins; Neovascularization, Pathologic; Signal Transduction; Female
Wang, Z., Perez, M., Caja, S., Melino, G., Johnson, T., Lindfors, K., et al. (2013). A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis. CELL DEATH & DISEASE, 4, e808-e808 [10.1038/cddis.2013.318].
Wang, Z; Perez, M; Caja, S; Melino, G; Johnson, T; Lindfors, K; Griffin, M
Articolo su rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/102688
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