Efeito do Maxadilan na célula endotelial: papel na permeabilidade vascular

Abstract

Recently, it was demonstratedthat saliva of Lutzomyialongipalpis, main vector of leishmaniosis, presents vasoactive components such as Maxadilan (MAX), a potent vasodilator that contributes Leishmaniainfectivity. The vasoactive and pro-inflammatory effects of maxadilan are mediated by its highly selective pituitary receptor type 1 (PAC1). Recent work from our group highlights the proinflammatory actions of maxadilan, showing that this peptide increases in vivo vascular permeability and leukocytesactivation in post-capillary venules. However, the effects of MAX in endothelial cells, as well the molecular mechanisms involved in these actions are not well described. This study aims to investigate the effects of MAX on endothelial cells. First, human microvascular (HMEC-1) were incubated in the absence or presence MAX and we demonstrated that this peptideis able to increase endothelial permeability in a PAC1 -dependent manner. In addition, MAX was able to promotephosphorylation and dispersion of VE-cadherin, inducing its internalization and subsequent β-catenin nuclear translocation. Also, MAX promoted reorganization of the actin cytoskeleton, redistribution of paxillin and its colocalization with actin in the focal adhesion, Furthermore, MAX inducesFAKphosphorylation at residue 397 and its association with actin. MAX induces Srctranslocation to membrane and its association with VE-cadherin in the adherens junctions. Finally, Src inhibition reducesthe effects of MAX in the endothelial permeability. Together, our data suggest that the inflammatory events induced by MAX involve the disruption of the endothelial barrier after interaction with PAC1 receptor. A better understanding of MAX effects on endothelium may leads to the development of more specific strategies for the leishmaniosis treatment and a new tool for the study of endothelial cell biology