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

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 5

Lack of endothelial FGF signaling impairs postischemic tissue recovery and arteriogenesis.

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Lack of endothelial FGF signaling impairs postischemic tissue recovery a...
(A) Tissue loss in FGFR1DN mice. After induction of FGFR1DN expression, hindlimb ischemia was produced by ligation of the right femoral artery in control and FGFR1DN mice. Photographs were taken 7 days after induction of ischemia. (B) Tissue loss score (0, healthy; 1, black nails; 2, black toes; 3, toe loss; 4, foot loss) at day 7. Data were analyzed by Wilcoxon rank-sum test (n = 20 [control]; 14 [FGFR1DN]; 12 [Ad–sFGFR1-IIIc and Ad–sFGFR3-IIIb]). Boxes denote interquartile range; lines within boxes denote median; symbols within boxes denote mean; whiskers denote 5th and 95th percentile; bars denote minimum and maximum. (C) Apoptosis in the ischemic muscle of FGFR1DN mice. 3 days after induction of ischemia, gastrocnemius muscle was taken and stained for TUNEL. Apoptotic nuclei (green) were widely distributed throughout muscle cells of FGFR1DN mice. Scale bars: 20 μm. (D) Percent TUNEL+ apoptotic cells relative to DAPI+ cells (n = 3 per group). (E) Laser Doppler analysis of perfusion in mice after hindlimb ischemia. Changes in perfusion are shown as a ratio of right to left hindlimb (n = 5 per group). Data are mean ± SEM. (F) Micro-CT reconstruction at 16-μm resolution of the calf and thigh portions of mouse hindlimbs 21 days after femoral artery ligation. Scale bar: 332 μm × 96 μm. (G) Quantitative analysis of micro-CT images in the calf, presented as total number of vascular structures in 250 z axis slices (n = 3 per group). Data are mean ± SEM. *P < 0.05, **P < 0.01 versus respective control.