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Hypoxia‐Induced Heparan Sulfate Primes the Extracellular Matrix for Cell Recruitment by Facilitating VEGF‐Fibronectin Interactions
Author(s) -
BuczekThomas Jo Ann,
Rich Celeste B.,
Nugent Matthew A.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.379.10
Subject(s) - fibronectin , extracellular matrix , angiogenesis , heparan sulfate , chemistry , microbiology and biotechnology , vascular endothelial growth factor , hypoxia (environmental) , extracellular , vascular endothelial growth factor a , kinase insert domain receptor , cell , biochemistry , biology , cancer research , vegf receptors , organic chemistry , oxygen
Vascular endothelial growth factor (VEGF) is a signaling protein that drives angiogenesis and the dysregulation of the VEGF system contributes to several disease states. With disease onset, extracellular matrices (ECM) experience dramatic changes in pH and composition that can affect cellular response. Within the ECM, fibronectin (Fn) is the major binding site for VEGF and heparan sulfate (HS) present in the ECM catalytically alters Fn structure to enhance VEGF‐Fn interactions and subsequent cell activation. In the present study, we investigated the role of heparan sulfate isolated from normoxic and hypoxic cells in modulating VEGF‐Fn interactions. For these studies, retinal pigmented epithelial (RPE) cells were cultured under normoxia or hypoxia (pO 2 1%; 72 hours) prior to HS isolation by chromatographic methods. ELISA analysis indicated that hypoxia treatment induced changes in the amount and structure of the HS produced. 125 I VEGF binding to Fn pretreated with normoxic or hypoxic HS indicated hypoxia‐derived HS enhanced VEGF binding to Fn while HS from normoxic cells lacked significant catalytic activity. VEGF receptor chimera binding assays indicated preferential binding of VEGF‐Fn to VEGFR2 over VEGFR1 and endothelial cell attachment was enhanced on RPE cells maintained under hypoxic conditions. These results indicate that hypoxia primes the ECM through the action of HS on Fn to become a depot for VEGF.