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2014 ; 289
(42
): 29044-59
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gab.com Text
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English Wikipedia
Genome-wide approaches reveal functional vascular endothelial growth factor
(VEGF)-inducible nuclear factor of activated T cells (NFAT) c1 binding to
angiogenesis-related genes in the endothelium
#MMPMID25157100
Suehiro J
; Kanki Y
; Makihara C
; Schadler K
; Miura M
; Manabe Y
; Aburatani H
; Kodama T
; Minami T
J Biol Chem
2014[Oct]; 289
(42
): 29044-59
PMID25157100
show ga
VEGF is a key regulator of endothelial cell migration, proliferation, and
inflammation, which leads to activation of several signaling cascades, including
the calcineurin-nuclear factor of activated T cells (NFAT) pathway. NFAT is not
only important for immune responses but also for cardiovascular development and
the pathogenesis of Down syndrome. By using Down syndrome model mice and clinical
patient samples, we showed recently that the VEGF-calcineurin-NFAT signaling axis
regulates tumor angiogenesis and tumor metastasis. However, the connection
between genome-wide views of NFAT-mediated gene regulation and downstream gene
function in the endothelium has not been studied extensively. Here we performed
comprehensive mapping of genome-wide NFATc1 binding in VEGF-stimulated primary
cultured endothelial cells and elucidated the functional consequences of
VEGF-NFATc1-mediated phenotypic changes. A comparison of the NFATc1 ChIP sequence
profile and epigenetic histone marks revealed that predominant NFATc1-occupied
peaks overlapped with promoter-associated histone marks. Moreover, we identified
two novel NFATc1 regulated genes, CXCR7 and RND1. CXCR7 knockdown abrogated
SDF-1- and VEGF-mediated cell migration and tube formation. siRNA treatment of
RND1 impaired vascular barrier function, caused RhoA hyperactivation, and further
stimulated VEGF-mediated vascular outgrowth from aortic rings. Taken together,
these findings suggest that dynamic NFATc1 binding to target genes is critical
for VEGF-mediated endothelial cell activation. CXCR7 and RND1 are NFATc1 target
genes with multiple functions, including regulation of cell migration, tube
formation, and barrier formation in endothelial cells.