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Heparin mediates conformational changes on fibronectin exposing vascular endothelial growth factor binding sites
Author(s) -
Mitsi Maria,
Hong Zhenning,
Costello Catherine E,
Nugent Matthew A
Publication year - 2006
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.20.4.a515-b
Subject(s) - fibronectin , heparin , extracellular matrix , heparan sulfate , angiogenesis , chemistry , chondroitin sulfate , glycosaminoglycan , microbiology and biotechnology , vascular endothelial growth factor , binding site , biophysics , biochemistry , conformational change , in vitro , biology , cancer research , vegf receptors
Interactions between components of the extracellular matrix and growth factors play critical roles in regulating angiogenesis. We conducted a detailed study of the interactions between fibronectin and vascular endothelial growth factor (VEGF) and investigated how heparin modulates these interactions using a combination of in vitro binding assays and atomic force microscopy. We found that fibronectin contains at least two binding sites for VEGF (K d ~ 200 nM) whose availability is determined by pH and the conformational state of fibronectin. Interactions between immobilized fibronectin and heparin or heparan sulfate, even for very short periods of time, promote a conformational change in fibronectin to form more elongated molecules with exposed VEGF binding sites, increasing VEGF binding. After the conformational change has occurred, the presence of heparin is not necessary to sustain the effect. Chondroitin sulfate as well as chemically desulfated derivatives of heparin and heparin fragments do not exhibit the same effect. Our data suggest a mechanism for heparin/heparan sulfate in regulating angiogenesis by modulating extracellular matrix structure and growth factor activity. (Supported by: NIH RO1 HL56200, NHI PO1 HL46902 and NCRR P41 RR10888).