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


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.

Publication DOI: https://doi.org/10.1038/cddis.2013.318;
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Aston University (General)
Additional Information: 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.
Uncontrolled Keywords: angiogenesis,crosslinking,tissue transglutaminase,tubule and VEGF,Cell Biology,Immunology,Cancer Research,Cellular and Molecular Neuroscience
Publication ISSN: 2041-4889
Last Modified: 27 Jun 2024 08:15
Date Deposited: 01 Oct 2013 13:36
Full Text Link: http://www.natu ... is2013318a.html
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2013
Published Online Date: 2013-09-19
Authors: Wang, Z. (ORCID Profile 0000-0002-2212-8318)
Perez, M.
Caja, S.
Melino, G.
Johnson, T.S.
Lindfors, K.
Griffin, M. (ORCID Profile 0000-0003-3824-306X)


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