title: Human microvascular pericyte basement membrane remodeling regulates neutrophil recruitment.
abstract: OBJECTIVE
  Neutrophil extravasation at post-capillary venules, consisting of EC, PC, and the shared ECM, increases following fibrotic remodeling in the lung, liver, and skin. The role of fibrotic pericyte-derived ECM in regulating EC activation and neutrophil recruitment remains unexplored.
  
  
  METHODS
  To elucidate the role of human pericyte-derived ECM in EC activation, we characterized PC-derived ECM following transforming growth factor-β1, IL-1β, CCL2, or bleomycin activation, and examined surface adhesion molecule expression and neutrophil recruitment by EC cultured on PC-ECM.
  
  
  RESULTS
  Pro-inflammatory activation of PC-induced deposition of compositionally distinct ECM compared with non-activated control. Bleomycin activation induced fibronectin-rich and collagen-poor ECM remodeling by PC, facilitating increased neutrophil transendothelial migration when compared with non-activated pericyte ECM (49.9 ± 3.4% versus 29.7 ± 1.4%). Increases in fibronectin compared to collagen I, are largely responsible for ECM-regulated neutrophil recruitment, as EC cultured on fibronectin supported increased neutrophil transmigration compared to collagen I (51.6 ± 6.2% versus 28.0 ± 4.8%). We attribute this difference to increased expression of ICAM-1 and its redistribution to EC borders.
  
  
  CONCLUSIONS
  This is the first demonstration of human pericyte sensitivity to inflammatory stimuli, inducing fibrotic matrix deposition that regulates EC adhesion molecule expression and neutrophil recruitment.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
authors.forename: Parid
authors.initials: P
authors.lastname: Sava
authors.forename: Ian O
authors.initials: IO
authors.lastname: Cook
authors.forename: Rajwant S
authors.initials: RS
authors.lastname: Mahal
authors.forename: Anjelica L
authors.initials: AL
authors.lastname: Gonzalez
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001485:Basement Membrane / Q000378:metabolism*; D001761:Bleomycin / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C573420:ICAM1 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D018799:Intercellular Adhesion Molecule-1
keywords: ICAM-1; extracellular matrix; fibronectin; fibrosis; transmigration