The FGF system has a key role in regulating vascular integrity
Masahiro Murakami, Loc T. Nguyen, Zhen W. Zhang, Karen L. Moodie, Peter Carmeliet, Radu V. Stan, Michael Simons
Masahiro Murakami, Loc T. Nguyen, Zhen W. Zhang, Karen L. Moodie, Peter Carmeliet, Radu V. Stan, Michael Simons
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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 2

Impaired vascular integrity in mice lacking FGF signaling.

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Impaired vascular integrity in mice lacking FGF signaling. (A) Increased...
(A) Increased vascular permeability and impaired endothelial morphology in sFGFR1IIIc mouse. Ten days after adenoviral injection in C57BL/6 mice, the trachea vasculature was stained for CD31 (red). Green represents microspheres in the extravascular space. Scale bars: 20 μm (left panels); 10 μm (right panels). (B) sFGFR1IIIc increases vascular permeability in the muscle. Ad-Null (control) or Ad-sFGFR was injected in C57BL/6 mice, and 14 days later, Evans blue dye was injected i.v. The adductor group muscles were harvested for quantitation. Data are shown as mean ± SD (n = 4). *P < 0.05, control vs. sFGFR1IIIc by t test. (C) Inhibition of FGF signaling in the heart and lung increases vascular permeability. Ad-Null (control), Ad-sFGFR was injected in C57BL/6 mice, and 10 days later, Evans blue dye levels were examined in the heart and lung. Data are shown as mean ± SD for n = 7, control; n = 8, sFGFR1IIIc; n = 4, sFGFR3IIIb; n = 4, sFGFR3IIIc. *P < 0.05, vs. control by t test. (D) Increased vascular permeability in Ad-sFGFR1IIIc–treated nude mouse. NU/NU nude mice (Charles River Laboratories) were subjected to trachea CD31. Junctional CD31 staining observed in control (arrows) is completely absent in the Ad-sFGFR1IIIc–treated trachea vasculature. Scale bars: 20 μm (left panels); 10 μm (right panels). (E) Hemorrhage observed in Ad-sFGFR1IIIc–treated mouse lung and heart. Ten days after adenoviral injection in nude mice, lung and heart were harvested for H&E staining. Upper panels show lung sections and lower panels show heart sections. Black arrows indicate myocardial hemorrhage. Original magnification, ×400.