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.
View: Text | PDF
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

×

Figure 6

Lack of endothelial FGF signaling impairs vascular integrity.

Options: View larger image (or click on image) Download as PowerPoint
Lack of endothelial FGF signaling impairs vascular integrity. (A) Micro-...
(A) Micro-CT images of arterial vasculature 3 days after femoral artery ligation. Arrows indicate leakage of the contrast agent. Scale bar: 332 μm × 96 μm. (B) Vascular leakage in the ischemic thigh of FGFR1DN mice. 3 days after induction of hindlimb ischemia, FITC-dextran (2 mDa) was injected into the carotid artery and visualized with fluorescent stereo-microscope. Arrows indicate sites of dextran extravasation; arrowheads indicate the primary branch of the femoral artery. (C) Quantitative analysis of vascular permeability. Evans blue dye was injected i.v. 3 days after hindlimb ischemia. Mice were then perfused with saline, and the lower part of adductor muscle was taken for quantification (n = 3 per group). (D) Quantitative real-time PCR analysis of Vegf2 expression using total RNA isolated from ischemic muscle of control or FGFR1DN mice harvested 7 days after hindlimb ischemia (n = 3 per group). *P < 0.05 versus control. (E) FGF-VEGFR2 interaction. Erk1/2 activated by FGF signaling translocates to the nucleus and promotes Ets binding to the FOX:ETS composite site in the first intron enhancer of Vegfr2. This results in increased VEGFR2 transcription and expression. In the absence of basal FGF signaling, VEGFR2 expression is downregulated, and thus angiogenic activity is decreased.