IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells

Abstract

Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody ( IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.

Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level

“…A difference in binding characteristics depending on the incorporated IR halfdimer, IRA or IRB, has been reported (Pandini et al, 2002), but recent studies suggest that both types of hybrid receptors have the same affinity for IGF-I and insulin (Benyoucef et al, 2007, Slaaby et al, 2006. The lack of insulin effect on DNA-synthesis in HMVEC is in agreement with our previous observation (Chisalita and Arnqvist, 2004) together with several other reports on microvascular cells (Artwohl et al, 2007, Giannini et al, 2001 suggesting that human microvascular endothelial cells are insulin resistant. Because of the cross-reactivity of insulin and IGF-I at high concentrations it is very important to use physiological or near physiological concentrations of the peptides when studying insulin and IGF-I effects in vitro on cells that express both IR types and IGF-IR, and also to make sure of which receptor is activated.…”

“…Other studies on microvascular endothelial cells suggest that HMVEC as well as glomerular (Giannini et al, 1999) and retinal microvascular endothelial cells (Giannini et al, 2001) are very sensitive to IGF-I indicating a physiological function of IGF-I.…”

Endothelial cells and the IGF system

“…Another study demonstrated that human retinal endothelial cells secrete IGFBP2, IGFBP3, IGFBP4 and IGFBP5 (Giannini et al 2001). GH, VEGF, FGF2 and PDGF had no effect on IGFBP levels, whereas IGF1 decreased IGFBP4 and increased IGFBP5 levels.…”

Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells

“…There is a lack of studies regarding effects of insulin and IGF-I on glucose metabolism and DNA synthesis in human endothelial cells. An effect of IGF-I on [ 3 H]thymidine incorporation into DNA has been reported in human retinal endothelial cells (14). The aim of our study was to characterize IR and IGF-IR in human micro-and macrovascular endothelial cells with regard to gene expression, ligand binding, receptor activation, and the biological effect of insulin, glargine, and IGF-I.…”