Fibroblast growth factor system regulates vascular integrity and endothelial permeability

Abstract

Background: We have recently shown that the fibroblast growth factor (FGF) system plays an essential role in the neovascularization process in adult mice. Methods: To further investigate the mechanism, we employed two models to disrupt FGF signaling: conditional transgenic mice expressing dominant-negative form of FGFR1 (FGF-R1DN) in the endothelium under the control of tetracycline regulated Tie2 promoter and systemic expression of soluble FGFR-IgFc chimera proteins (sFGFR) in mice. Results: Micro-CT and fluorescent stereo-microscope analyses demonstrated vascular leakage after the ischemic injury in FGF-R1DN mice. Introduction of sFGFR1IIIc confirmed increased vascular permeability in non-ischemic tissues. The artery infected with Ad-FGF-R1DN showed disrupted endothelium and cell-cell junctions as demonstrated by enface immunostaining and scanning electron microscopy (SEM). In vitro studies demonstrated that FGF stimulation enhances endothelial barrier function, whereas inhibition of FGF signaling leads to increased VE-cadherin phosphorylation and disassembly of VE-cadherin-catenin complex. This resulted in disorganized endothelial junctions and increased permeability. Conclusion: The FGF system controls endothelial barrier function by regulating junctional protein dynamics, which in turn plays an important role in the maintenance of vascular integrity.