RT Journal Article SR Electronic T1 The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP e1500175 DO 10.1126/sciadv.1500175 VO 1 IS 3 A1 Hahn, Cornelia S. A1 Scott, David W. A1 Xu, Xin A1 Roda, Mojtaba Abdul A1 Payne, Gregory A. A1 Wells, J. Michael A1 Viera, Liliana A1 Winstead, Colleen J. A1 Bratcher, Preston A1 Sparidans, Rolf W. A1 Redegeld, Frank A. A1 Jackson, Patricia L. A1 Folkerts, Gert A1 Blalock, J. Edwin A1 Patel, Rakesh P. A1 Gaggar, Amit YR 2015 UL http://advances.sciencemag.org/content/1/3/e1500175.abstract AB The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability. N-α-PGP activates human endothelial cells via CXC-chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway. In vivo, N-α-PGP induces local vascular leak after subcutaneous administration and pulmonary vascular permeability after systemic administration. Furthermore, neutralization of N-α-PGP attenuates lipopolysaccharide-induced lung leak. Finally, we demonstrate that plasma from patients with acute respiratory distress syndrome (ARDS) induces VE-cadherin phosphorylation in human endothelial cells, and this activation is attenuated by N-α-PGP blockade with a concomitant improvement in endothelial monolayer impedance. These results identify N-α-PGP as a novel ECM-derived matrikine regulating paracellular permeability during inflammatory disease and demonstrate the potential to target this ligand in various disorders characterized by excessive matrix turnover and vascular leak such as ARDS.