The FGF system has a key role in regulating vascular integrity
Masahiro Murakami, … , Radu V. Stan, Michael Simons
Masahiro Murakami, … , Radu V. Stan, Michael Simons
Published September 5, 2008
Citation Information: J Clin Invest. 2008;118(10):3355-3366. https://doi.org/10.1172/JCI35298.
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Research Article Vascular biology

The FGF system has a key role in regulating vascular integrity

Abstract

The integrity of the endothelial monolayer is essential to blood vessel homeostasis and active regulation of endothelial permeability. The FGF system plays important roles in a wide variety of physiologic and pathologic conditions; however, its role in the adult vasculature has not been defined. To assess the role of the FGF system in the adult endothelial monolayer, we disrupted FGF signaling in bovine aortic endothelial cells and human saphenous vein endothelial cells in vitro and in adult mouse and rat endothelial cells in vivo using soluble FGF traps or a dominant inhibitor of all FGF receptors. The inhibition of FGF signaling using these approaches resulted in dissociation of the VE-cadherin/p120-catenin complex and disassembly of adherens and tight junctions, which progressed to loss of endothelial cells, severe impairment of the endothelial barrier function, and finally, disintegration of the vasculature. Thus, FGF signaling plays a key role in the maintenance of vascular integrity.

Authors

Masahiro Murakami, Loc T. Nguyen, Zhen W. Zhang, Karen L. Moodie, Peter Carmeliet, Radu V. Stan, Michael Simons

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Figure 1

Validation of the sFGFR system.

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Validation of the sFGFR system. (A) sFGFR blocks FGF-induced Erk1/2 phos...
(A) sFGFR blocks FGF-induced Erk1/2 phosphorylation in vitro in a dose-dependent manner. Ad-GFP and Ad-sFGFR1IIIc were transduced in BAECs and stimulated with indicated concentration of FGF1 for 10 minutes. Total cell lysates were subjected to Western blotting. p-Erk1/2, phospho-Erk1/2; t-Erk1/2, total Erk1/2; VP, viral particles. (B) sFGFRs effectively inhibit FGF1-induced Erk1/2 activation. Ad-Null, Ad-sFGFR1IIIc, Ad-sFGFR3IIIb, and Ad-sFGFR3IIIc were transduced in BAECs and stimulated with FGF1 for 5 minutes. (C) sFGFR3IIIb does not inhibit FGF2-induced Erk1/2 activation. Ad-Null and Ad-sFGFRs were transduced in BAECs and stimulated with FGF2 for 5 minutes. (D) Plasma expression levels of sFGFR in mice. Ad-Null (control) or Ad-sFGFR1IIIc (5 × 1010 viral particles) was injected into C57BL/6 mice, and blood samples were taken at indicated time points. sFGFR levels were measured using an ELISA system detecting human IgG-Fc. Data are shown as mean ± SD, n = 4 in each group. (E) Tissue distribution of sFGFR. After 10 days of Ad-Null (control) or Ad-sFGFR1IIIc injection (5 × 1010 viral particles), tissue samples were collected and total protein was extracted. Thereafter, ELISA assays detecting human IgG-Fc were performed. Data are shown as mean ± SD, 4 animals in each group. (F) Body weight change after injection of sFGFR. Ten-week-old C57BL/6 mice were injected with adenoviruses (5 × 1010 viral particles), and body weight was measured weekly. Data are shown as mean ± SD, n = 4 in each group. *P < 0.05, Student’s t test.