Abstract
Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bß15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bß15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bß15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bß15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bß15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bß15-42 is confirmed in Fyn−/− mice, where the peptide is unable to reduce LPS-induced lung edema, whereas in wild type littermates the peptide significantly reduces leak. Our results demonstrate a novel function for Bß15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock.
Highlights
Capillary leak may be transient, as seen in response to histamine or prolonged as seen in response to thrombin [1]
Dengue shock syndrome (DSS) in humans is characterized by progressive capillary leak [24,25]
Animals treated with FX06 had significantly improved survival rates (Fig. 1A), significantly reduced capillary leak within lungs and the intestine (Fig. 1D) and significantly reduced hemoconcentration and fibrinogen consumption (Fig. 1C)
Summary
Capillary leak may be transient, as seen in response to histamine or prolonged as seen in response to thrombin [1]. Extensive leakage often occurs in intensive care patients and is thought to be caused by the exposure of endothelial cells to activated coagulation factors (e.g., thrombin) plus pro-inflammatory stimuli (VEGF, LPS, and others). This results in endothelial cell activation, downregulation of thrombin inhibitors and activation of the small GTPase RhoA. By regulating levels of myosin light chain phosphorylation and actin stress fiber formation RhoA controls cell contraction [1,7,8,9]. VEcadherin is directly connected to the actin-based cytoskeleton and is one of the key molecules integrating signals for opening and tightening of cell junctions [15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
