Yulia A. Komarova

Department of Pharmacology, University of Illinois at Chicago, 835 S Wolcott, E403 MSB, Chicago, USA


Abstract:

We have shown that Vascular Endothelial (VE)-cadherin outside-in signaling regulates phosphorylation of End Binding (EB) protein 3 to suppress Microtubule (MT) persistent growth and assemble adherens junctions (AJs). Depletion of EB3 has no effect on either MT dynamics or formation of AJs in contiguous endothelium but significantly attenuates cell shape change and permeability increase in response to pro-inflammatory mediators. EB3 interacts with inositol 1,4,5-thriphosphate receptor type 3 (IP3R3) and facilitates IP3-dependent release of calcium from intracellular stores. Based on the crystal structure of the EB interacting domain and using the computational alanine scan approach, we designed a 7-amino acid EB inhibitory peptide (EBIN) that mimics interaction between EB3 and IP3R3. Cell permeant variant of EBIN reduces the interaction between EB3 and IP3R3 and mitigated increased endothelial permeability response. Furthermore, infusion of this peptide in ex vivo murine lung preparation attenuates the increase in lung vascular liquid permeability (Kf,c) in response to activation of the Protease-Activated Receptor-1 (PAR-1). Intravenous injection of this peptide prevents lung injury and reduces the lethality of polymicrobial sepsis in mice. These data indicate that EBIN can be used as a novel therapy to prevent leaky vessel syndrome during inflammation.