Endothelial barrier stabilization by a cyclic tandem peptide targeting VE-cadherin transinteraction in vitro and in vivo
WM Heupel, A Efthymiadis, N Schlegel… - Journal of cell …, 2009 - journals.biologists.com
Journal of cell science, 2009•journals.biologists.com
Inflammatory stimuli result in vascular leakage with potentially life threatening
consequences. As a key barrier component, loss of vascular endothelial (VE-) cadherin-
mediated adhesion often precedes endothelial breakdown. This study aimed to stabilize VE-
cadherin transinteraction and endothelial barrier function using peptides targeting the VE-
cadherin adhesive interface. After modelling the transinteracting VE-cadherin structure, an
inhibiting single peptide (SP) against a VE-cadherin binding pocket was selected, which …
consequences. As a key barrier component, loss of vascular endothelial (VE-) cadherin-
mediated adhesion often precedes endothelial breakdown. This study aimed to stabilize VE-
cadherin transinteraction and endothelial barrier function using peptides targeting the VE-
cadherin adhesive interface. After modelling the transinteracting VE-cadherin structure, an
inhibiting single peptide (SP) against a VE-cadherin binding pocket was selected, which …
Inflammatory stimuli result in vascular leakage with potentially life threatening consequences. As a key barrier component, loss of vascular endothelial (VE-) cadherin-mediated adhesion often precedes endothelial breakdown. This study aimed to stabilize VE-cadherin transinteraction and endothelial barrier function using peptides targeting the VE-cadherin adhesive interface. After modelling the transinteracting VE-cadherin structure, an inhibiting single peptide (SP) against a VE-cadherin binding pocket was selected, which specifically blocked VE-cadherin transinteraction as analyzed by single molecule atomic force microscopy (AFM). The tandem peptide (TP) consisting of two SP sequences in tandem was designed to strengthen VE-cadherin adhesion by simultaneously binding and cross-bridging two interacting cadherin molecules. Indeed, in AFM experiments TP specifically rendered VE-cadherin transinteraction resistant against an inhibitory monoclonal antibody. Moreover, TP reduced VE-cadherin lateral mobility and enhanced binding of VE-cadherin-coated microbeads to cultured endothelial cells, but acted independently of the actin cytoskeleton. TP also stabilized endothelial barrier properties against the Ca2+ ionophore A23187 and the inhibitory antibody. Finally, TP abolished endothelial permeability increase induced by tumour necrosis factor-α in microperfused venules in vivo. Stabilization of VE-cadherin adhesion by cross-bridging peptides may therefore be a novel therapeutic approach for the treatment of vascular hyperpermeability.
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