title: Fibroblast growth factor-2 binding to the endothelial basement membrane peaks at a physiologically relevant shear stress.
abstract: Fibroblast growth factor-2 (FGF2) is produced and released by endothelial cells and binds to heparan sulfate proteoglycans in the endothelial basement membrane (BM), an important FGF2 storage reservoir. Experimental and computational models of FGF2 binding kinetics to both cells and BM under static conditions are well established in the literature but remain largely unexplored under flow. We now examine BM-FGF2 binding kinetics in fluid flow conditions. We hypothesized that FGF2 binding to the endothelial BM would decrease as fluid shear stress increased. To investigate this, BM-FGF2 equilibrium, associative, and dissociative bindings were measured at various shear stresses. Surprisingly, FGF2 binding increased up to a physiological arterial shear stress of 25 dynes/cm², after which it decreased to a level similar to the 1 dyne/cm² condition. Both BM-FGF2 dissociation and BM binding site availability increased with flow, while association remained constant. This suggests that force-dependent FGF2 equilibrium binding varies with shear stress due to a combination of an increase in binding site availability and FGF2 dissociation with flow. This improved understanding of BM-FGF2 binding with flow enriches current knowledge of FGF2 binding kinetics under physiologic conditions, which may contribute to improved growth factor therapy development.
authors.affiliation: Department of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Reisig
authors.forename: Alisa Morss
authors.initials: AM
authors.lastname: Clyne
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005898:Glass / Q000737:chemistry; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D007700:Kinetics; D008858:Microscopy, Phase-Contrast; D011485:Protein Binding / Q000502:physiology; D012212:Rheology; D034421:Sus scrofa
chemical_list: D019812:Heparan Sulfate Proteoglycans; D016222:Fibroblast Growth Factor 2