Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

Helen L Spencer, Eva Jover, William Cathery, Elisa Avolio, Iker Rodriguez-Arabaolaza, Anita C Thomas, Valeria V Alvino, Graciela Sala-Newby, Zexu Dang, Marco Fagnano, Carlotta Reni, Jonathan Rowlinson, Rosa Vono, Gaia Spinetti, Antonio P Beltrami, Cesare Gargioli, Andrea Caporali, Gianni Angelini, Paolo Madeddu

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Objective- To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results- Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2. TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis. Conclusions- TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis.

Original languageEnglish
Pages (from-to)1113-1124
Number of pages12
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume39
Issue number6
Early online date25 Apr 2019
DOIs
Publication statusPublished - 1 Jun 2019

Structured keywords

  • Centre for Surgical Research

Keywords

  • aspartic acid
  • endothelial cells
  • glycoproteins
  • immunohistochemistry
  • pericytes

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  • Cite this

    Spencer, H. L., Jover, E., Cathery, W., Avolio, E., Rodriguez-Arabaolaza, I., Thomas, A. C., Alvino, V. V., Sala-Newby, G., Dang, Z., Fagnano, M., Reni, C., Rowlinson, J., Vono, R., Spinetti, G., Beltrami, A. P., Gargioli, C., Caporali, A., Angelini, G., & Madeddu, P. (2019). Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(6), 1113-1124. https://doi.org/10.1161/ATVBAHA.119.312665