Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: potential mechanism for maintenance of an avascular environment.
Aqueous humor is a clear fluid, primarily a blood filtrate, which circulates through the anterior chamber of the eye and bathes the cornea. We explored the possibility that components in the aqueous humor play a direct part in maintaining the avascular environment of the cornea. We report here that heparan sulfate proteoglycan (HSPG) was found in bovine aqueous humor and that it directly inhibits binding of basic fibroblast growth factor and vascular endothelial growth factor to cell-surface heparan sulfate. We demonstrate that this holds true for all heparin binding proteins tested but not for epidermal growth factor, which does not bind heparin. Furthermore, we show, with mathematical modeling, that the concentration of HSPG in aqueous humor (approximately 4 microg/ml), when combined with the clearance of aqueous humor from the eye due to circulation, is sufficient to block the binding of heparin binding growth factors to corneal endothelium. This mechanism suggests a physiological process to control bioavailability of angiogenic growth factors in the cornea.
Fannon
Michael
M
Department of Surgery, The Children's Hospital, 300 Longwood Ave., Boston, Massachusetts 02115, USA. michael.fannon@tch.harvard.edu
Forsten-Williams
Kimberly
K
Dowd
Christopher J
CJ
Freedman
Deborah A
DA
Folkman
Judah
J
Nugent
Matthew A
MA
D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry*; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D008954:Models, Biological; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase