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

作者：Mena Mari Pau; Papiewska Pajak Izabela^*; Przygodzka Patrycja; Kozaczuk Anna; Boncela Joanna; Cierniewski Czeslaw S

来源：Experimental Cell Research, 2014, 324(2): 124-136.

DOI：10.1016/j.yexcr.2014.03.008

• Inflammation
• Angiogenesis
• VEGF-A
• TNF-alpha
• NFAT
• Integrins
• COX-2

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-alpha. Two groups of integrin subunits specifically upregulated over time by both cytokines were identified using RT-PCR and Western Immunoblotting. The first group included alpha 4, alpha 5, alpha 6, and 135 subunits that were upregulated by VEGF-A; the second group consisted of alpha V and 133 induced by TNF-alpha. Both cytokines significantly enhanced the expression of 31 and modulated alpha 2 mRNA. In contrast to TNF-alpha, VEGF-A induction of integrin subunits depended on the activation of the calcineurin/NFAT pathway. Both calcineurin inhibitors (cyclosporineA and 11R-VIVIT) and down-regulation 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 alpha 2 beta 1, alpha 5 beta 1, Apt alpha 6 beta 1 and alpha V beta 5, which are involved at different stages of angiogenesis.

• 出版日期2014-6-10
• 单位河北医科大学