Fibrinogen-γ C-Terminal fragments induce endothelial barrier dysfunction and microvascular leak via integrin-mediated and RhoA-dependent mechanism

Mingzhang Guo, Dayle Daines, Jing Tang, Qiang Shen, Rachel M. Perrin, Yoshikazu Takada, Sarah Y. Yuan, Mack H. Wu

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Objectives - The purposes of this study were to characterize the direct effect of the C-terminal fragment of fibrinogen γ chain (γC) on microvascular endothelial permeability and to examine its molecular mechanism of action. Methods and Results-Intravital microscopy was performed to measure albumin extravasation in intact mesenteric microvasculature, followed by quantification of hydraulic conductivity in single perfused micro vessels. Transendothelial electric resistance was measured in microvascular endothelial cells in combination with immunoblotting and immunocytochemistry. The results show that γC induced time- and concentration-dependent increases in protein transvascular flux and water permeability and decreases in endothelial barrier function, coupled with Rho GTPase activation, myosin light chain phosphorylation, and stress fiber formation. Depletion of RhoA via siRNA knockdown or pharmacological inhibition of RhoA signaling attenuated γC-induced barrier dysfunction. Imaging analyses demonstrated binding of γC to endothelial cells; the interaction was inhibited during blockage of the αvβ3 integrin. Furthermore, in vivo experiments showed that the microvascular leak response to γC was attenuated in integrin β3 -/- animals. Conclusion-Fibrinogen-γ C terminus directly interacts with the microvascular endothelium causing fluid and protein leak. The endothelial response to γC involves an integrin receptor-mediated RhoA-dependent signaling pathway that leads to paracellular hyperpermeability.

Original languageEnglish
Pages (from-to)394-400
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number3
DOIs
Publication statusPublished - Mar 2009
Externally publishedYes

Keywords

  • Fibrinogen degradation products
  • Microvascular permeability
  • Rho-GTPase
  • Signal transduction
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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