title: NFAT2 regulates COX-2 expression and modulates the integrin repertoire in endothelial cells at the crossroads of angiogenesis and inflammation.
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.
authors.affiliation: Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland.
authors.forename: Mari-Pau
authors.initials: MP
authors.lastname: Mena
authors.affiliation: Institute 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.
authors.forename: Izabela
authors.initials: I
authors.lastname: Papiewska-Pajak
authors.affiliation: Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Przygodzka
authors.affiliation: Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kozaczuk
authors.affiliation: Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Boncela
authors.affiliation: Institute of Medical Biology, Polish Academy of Science, Lodz 93-232, Poland; Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz, Poland.
authors.forename: Czeslaw S
authors.initials: CS
authors.lastname: Cierniewski
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D016023:Integrins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Angiogenesis; COX-2; Inflammation; Integrins; NFAT; TNF-α; VEGF-A