Microcystin-leucine arginine blocks vasculogenesis and angiogenesis through impairing cytoskeleton and impeding endothelial cell migration by downregulating integrin-mediated Rho/ROCK signaling pathway

Abstract The main characteristic of eutrophication is cyanobacteria harmful algae blooms. Microcystin-leucine arginine (MC-LR) is considered to be the most toxic and most commonly secondary metabolite produced by cyanobacteria. It has been reported that MC-LR had potential vascular toxicity. However, the mechanism that MC-LR induced vascular toxicity is very limited and remain to be clarified. The aim of this study was to evaluate the toxic hazard towards the vasculogenesis and angiogenesis of MC-LR. Its effects on vasculogenesis, sprouting angiogenesis and endothelial cell tube formation were studied. The study showed that MC-LR exposure blocked vasculogenesis in zebrafish embryos, sprouting angiogenesis from rat aorta and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, MC-LR exposure also induced the disruption of cytoskeletal structures and markedly inhibited endothelial cells (ECs) migration from caudal hematopoietic tissue in zebrafish and HUVEC migration. Western blot analysis showed that MC-LR exposure down-regulated the expressions of integrin β1, FAK, Rho and ROCK. Combined with these results, MC-LR could induce disruption of cytoskeleton via down-regulating integrin-mediated FAK/ROCK signaling pathway, leading to the inhibition of ECs migration, which finally blocked vasculogenesis and angiogenesis.