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FGF-dependent regulation of VEGF receptor 2 expression in mice
Masahiro Murakami, … , Brian L. Black, Michael Simons
Masahiro Murakami, … , Brian L. Black, Michael Simons
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2668-2678. https://doi.org/10.1172/JCI44762.
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Research Article Vascular biology Article has an altmetric score of 6

FGF-dependent regulation of VEGF receptor 2 expression in mice

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Abstract

Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.

Authors

Masahiro Murakami, Loc T. Nguyen, Kunihiko Hatanaka, William Schachterle, Pei-Yu Chen, Zhen W. Zhuang, Brian L. Black, Michael Simons

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Figure 2

FGF signaling controls VEGFR2 enhancer activity and expression of other endothelial genes.

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FGF signaling controls VEGFR2 enhancer activity and expression of other ...
(A) BAECs were first transduced with Ad-Null or Ad-FGFR1DN and subsequently with Ad–ME-LA, and transfected with the luciferase reporter construct containing Vegfr2 first intron enhancer and minimal promoter. (B) Luciferase reporter assay using BAECs transduced with Ad-Null or Ad-FGFR1DN and transfected with the WT Vegfr2 enhancer or minimal promoter constructs carrying Ets binding site mutations (Pea3, G56T_G57T; Ets1, G303T_G304T; FOX:ETS, C378A_C379A). (C) Decreased enhancer activity by mutation of the FOX:ETS site was not rescued by constitutively active Erk2. (D) ChIP assay of Ets1 and Etv2 binding to VEGFR2 enhancer in BAECs (untransfected or transfected with Myc-tagged Etv2). Input DNA, sample representing total input chromatin (1%). (E–H) Quantitative RT-PCR analysis of total RNA isolated from BAECs transduced with Ad-Null or Ad-FGFR1DN. Values denote abundance relative to that of Ad-Null (assigned as 1). (I–L) Quantitative RT-PCR analysis of total RNA isolated from BAECs transduced with Ad-ME or Ad–ME-LA. *P < 0.05 versus respective control or as indicated by brackets, Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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