Altered distribution of basic fibroblast growth factor in diabetic retinopathy
A. Hanneken, E. de Juan Jr, G. A. Lutty, G. M. Fox, S. Schiffer and L. M. Hjelmeland
Department of Molecular and Cellular Growth Biology, Whittier Institute for Diabetes and Endocrinology, La Jolla, Calif 92037.
Basic fibroblast growth factor (FGF) is a potent endothelial cell mitogen
that has been proposed to play a role in proliferative diabetic retinopathy
and other neovascular processes. Our understanding of the in vivo role of
basic FGF in the pathogenesis of these disorders is limited. We studied the
immunolocalization of basic FGF in 16 clinical cases of diabetic
retinopathy to determine whether the normal retinal distribution of basic
FGF changed during the development of diabetic retinopathy and correlated
with the onset of retinal neovascularization. By using monoclonal and
affinity-purified polyclonal antibodies against basic FGF and heparan
sulfate proteoglycan (HSPG), we found that basic FGF colocalized with HSPG
to vascular basement membranes. As the basement membranes thickened during
the progression of diabetic retinopathy, the intraretinal stores of
immunoreactive basic FGF and HSPG expanded. With the development of
neovascularization, the colocalization of basic FGF and HSPG changed; HSPG
localized to basement membranes, while basic FGF localized intracellularly,
with only minimal basement membrane immunoreactivity. Incubations of the
neovascular fronds with exogenous basic FGF demonstrated multiple HSPG
glycosaminoglycan-binding sites for basic FGF, indicating that basic FGF
had not been released from the matrix of neovascular fronds by heparitanase
digestion.
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