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Exp Cell Res. 2014 Jun 10;324(2):124-36. doi: 10.1016/j.yexcr.2014.03.008. Epub 2014 Mar 18.

NFAT2 regulates COX-2 expression and modulates the integrin repertoire in endothelial cells at the crossroads of angiogenesis and inflammation.

Author information

  • 1Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland.
  • 2Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland; Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz, Poland. Electronic address: ipapiewska-pajak@cbm.pan.pl.
  • 3Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland; Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz, Poland.

Abstract

The mechanisms controlling the switch between the pro-angiogenic and pro-inflammatory states of endothelial cells are still poorly understood. In this paper, we show that: (a) COX-2 expression induced by VEGF-A is NFAT2-dependent; and (b) the integrin profile in endothelial cells induced by the pro-angiogenic VEGF-A is distinct from that brought on by the inflammatory cytokine TNF-α. Two groups of integrin subunits specifically upregulated over time by both cytokines were identified using RT-PCR and Western Immunoblotting. The first group included α4, α5, α6, and β5 subunits that were upregulated by VEGF-A; the second group consisted of αV and β3 induced by TNF-α. Both cytokines significantly enhanced the expression of β1 and modulated α2 mRNA. In contrast to TNF-α, VEGF-A induction of integrin subunits depended on the activation of the calcineurin/NFAT pathway. Both calcineurin inhibitors (cyclosporineA and 11R-VIVIT) and downregulation of NFAT2 with specific siRNA decreased induction of integrin subunits. This process of induction could be increased by upregulation of NFAT2 by pBJ5-NFAT2 transfection. This suggests that NFAT2 mediates VEGF-induced upregulation of integrin subunit synthesis by providing a constant supply of newly synthesized "refreshed" mature integrin receptors, particularly α2β1, α5β1, α4β1, α6β1 and αVβ5, which are involved at different stages of angiogenesis.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

Angiogenesis; COX-2; Inflammation; Integrins; NFAT; TNF-α; VEGF-A

PMID:
24657343
[PubMed - indexed for MEDLINE]
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