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.