Proceedings Of The National Academy Of Sciences Of The United States Of America
Vasculardysfunctionhasbeenreportedinhumancasesofanthrax, inmammalianmodelsofBacillusanthracis,andinanimalsinjected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrash model that permits in vivo imaging and evaluation of vasculature and cardiovascularfunction.Vasculardefectsmonitoredinhundredsof embryos enabled us to dene four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin actionbytrackingtheextravasationofuorescentmicrospheresin toxin-injected embryos. Lethal toxin did not induce a signicant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/ vascularpermeabilityfactor(VPF)signalingpathway,andwewere able to attenuate anthrax lethal toxin effects with chemical inhibitorsofVEGFRfunction.Ourstudydemonstratestheimportanceof vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.