THE C‐TERMINAL GLOBULAR DOMAIN OF FIBRINOGEN γ CHAIN INDUCES ENDOTHELIAL BARRIER DYSFUNCTION AND MICROVASCULAR LEAKAGE VIA A RHOA‐DEPENDENT MECHANISM

Abstract

Fibrinogen degradation products have been associated with endothelial dysfunction in inflammation. There is evidence that the C‐terminal globular domain of fibrinogen γ chain (γC) binds to endothelial cells, however, its functional impact on vascular barrier properties remains poorly understood. We examined the effects of recombinant γC on microvascular endothelial permeability using in vivo and in vitro models. The results showed that γC increased hydraulic conductivity and albumin permeability in rat mesenteric microvessels. In addition, γC induced endothelial monolayer barrier dysfunction in a dose‐dependent manner, concomitantly with endothelial Rho GTPase activation, myosin light chain phosphorylation, and stress fiber formation. Blockage of RhoA signaling with Y27632 inhibited the γC‐induced endothelial barrier dysfunction and microvascular leakage. Likewise, depletion of RhoA with siRNA prevented the hyperpermeability response. In contrast, the full‐length fibrinogen protein and the C‐terminal globular domains of fibrinogen αE and β chains did not cause significant changes in endothelial barrier function or microvascular permeability. Taken together, the results suggest that γC exerts a direct effect on the microvascular endothelium causing hyperpermeability via a RhoA‐dependent signaling pathway. Supported by NIH RO1 HL‐073324, HL‐061507 and HL‐070752.