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Increased Vitreous Concentrations of Human Hepatocyte Growth Factor in Proliferative Diabetic Retinopathy¹

Department of Clinical and Laboratory Medicine (M.N., M.U., A.N., M.Y.), Department of Ophthalmology (T.I., S.K.), Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan

Address all correspondence and requests for reprints to: Masato Nishimura, M.D., Department of Clinical and Laboratory Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan. E-mail: nishim{at}labmed.kpu-m.ac.jp

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Human hepatocyte GF (hHGF) has strong neoangiogenesis activity. The present study was designed to investigate the possible involvement of hHGF in neovascularization in proliferative diabetic retinopathy (PDR) by measuring vitreous hHGF concentrations. The mean vitreous hHGF concentration was higher in subjects with PDR (5.70 ± 0.68 ng/mL, n = 33) than in nondiabetic control subjects (1.50 ± 0.20 ng/mL, n = 18, P < 0.01), nondiabetic subjects with proliferative vitreoretinopathy (3.31 ± 0.57 ng//mL, n = 10, P < 0.05), or diabetic subjects without PDR (1.29 ± 0.28 ng/mL, n = 8, P < 0.01). PDR subjects with neovascularization of iris, which suggests advanced retinal ischemia, showed a higher mean vitreous hHGF concentration than those without iridal neovascularization [7.33 ± 1.16 ng/mL (n = 14) vs. 4.49 ± 0.72 ng/mL (n = 19), P < 0.05]. The mean vitreous hHGF concentration was higher in PDR subjects with retinal neovascularization at the optic disc than in those with neovascularization elsewhere [7.3 ± 1.1 ng/mL (n = 15) vs. 4.4 ± 0.7 ng/mL (n = 18), P < 0.05]. Our results indicate that vitreous hHGF may play a role in retinal neovascularization in PDR.

	Introduction

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PROLIFERATIVE diabetic retinopathy (PDR) is a major cause of adult blindness, and retinal neovascularization is the hallmark of PDR (1). Numerous mitogenic and angiogenic factors have been demonstrated to be present in the eye, including insulin-like growth factors, transforming growth factor-ß (TGF-ß), fibroblast growth factor, tumor necrosis factor, and vascular endothelial growth factor (VEGF) (2, 3, 4, 5, 6). Hepatocyte growth factor (HGF), which is identical to scatter factor (7, 8), is a disulfide-linked heterodimeric molecule composed of a 69-kDa kringle-containing -chain and a 34-kDa ß-chain (9, 10). The HGF receptor is the c-met protooncogene product, a transmembrane tyrosine kinase (11). Although HGF has been well characterized as a hepatotrophic (12, 13) and renotrophic factor (14, 15) in liver and kidney regeneration, the presence of the local HGF system (HGF and its receptor, c-met) has been demonstrated in both endothelial cells and vascular smooth muscle cells in vivo and in vitro (16). Recent studies indicate that human HGF (hHGF) is a powerful inducer of angiogenesis (17, 18). Moreover, hHGF may contribute to the genesis of AIDS-associated Kaposi’s sarcoma, a cytokine-dependent neoplasm characterized by a major component of neovascularization (19). Based on these findings, we asked whether hHGF may be involved in neovascularization in PDR.

The diffusible factors associated with angiogenesis in the eye should be present within the vitreous (3). To investigate whether vitreous concentrations of hHGF may be associated with neovascularization in PDR, we assayed vitreous hHGF concentrations in patients undergoing pars plana vitrectomy for advanced PDR or other vitreo-retinal diseases not associated with neovascularization.

	Subjects and Methods

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Vitreous samples were collected from subjects undergoing pars plana vitrectomies performed in the ophthalmologic department of Kyoto Prefectural University of Medicine. No patients enrolled in this study had severe hepatic or renal disease, which could affect the serum concentration of hHGF. The study was approved by the Ethical Committee for Human Research of Kyoto Prefectural University of Medicine, and all subjects provided informed consent for participation.

Nondiabetic control subjects

Nine female and nine male nondiabetic control subjects were studied [mean age, 62 ± 11 (SD) yr]. Pars plana vitrectomy was performed because of an idiopathic macular hole (n = 15) or rhegmatogenous retinal detachment (n = 3). No patient in this group had either iris neovascularization or fibrovascular retinal proliferation in the operated eye, and none received medical treatment except for their eye disease.

Nondiabetic subjects with proliferative vitreoretinopathy

Six female and four male subjects with proliferative vitreoretinopathy were studied [mean age, 61 ± 10 (SD) yr]. All subjects in this group had severe fibrous proliferation in both the retina and the vitreous, which had followed rhegmatogenous retinal detachment. None had iridal neovascularization or new vessel formation in the operated eye.

Diabetic subjects

Eight diabetic subjects without PDR and 33 diabetic subjects with PDR were studied. Diabetic subjects without PDR [4 females and 4 males; mean age, 59 ± 13 (SD) yr] had background diabetic retinopathy, and pars plana vitrectomy was performed for treatment of a macular hole. No patient in this group had iridal neovascularization or fibrovascular proliferation in the operated eye. The diabetic patients with PDR [18 females and 15 males; mean age, 53 ± 12 (SD) yr] were divided into subgroups according to the presence of iridal neovascularization or vitreous hemorrhage, the degree of retinal neovascularization, the area of retinal fibrous proliferation, or the extent of previous retinal photocoagulation; changes in vitreous hHGF concentration then were compared among subgroups (Fig. 1, Table 1). Of the 33 PDR patients, 14 had iridal neovascularization, 25 had tractional retinal detachments combined with vitreous hemorrhage, 7 had tractional retinal detachment without vitreous hemorrhage, and 1 had vitreous hemorrhage without retinal detachment. All diabetic subjects, with or without PDR, suffered from type II diabetes mellitus and had been treated with either insulin or sulfonylurea antidiabetic drugs. Mean serum glycosylated hemoglobin A1c values at the time of operation were 7.2 ± 0.4% in subjects without PDR, and 7.7 ± 0.2% in subjects with PDR.

View larger version (21K): [in this window] [in a new window]   Figure 1. Vitreous concentrations of hHGF in nondiabetic control subjects, nondiabetic subjects with proliferative vitreoretinopathy (PVR), diabetic subjects without PDR (Non PDR), and subjects with PDR with or without iridal neovascularization (iris neovasc). DM, Diabetes mellitus; *, P < 0.05; **, P < 0.01.

Before intraocular infusion, the vitreous core was cut and aspirated via the pars plana, with a vitreous cutter, and collected undiluted. Vitreous samples were spun for 15 min at 13,000 x g in a refrigerated centrifuge at 4 C to remove particles and then were stored in aliquots in polypropylene tubes at -80 C until assay.

Vitreous concentrations of hHGF

Vitreous concentrations of hHGF were measured by a specific enzyme-linked immunosorbent assay kit (Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan); intra- and interassay variations were 2.9% and 2.6%, respectively.

Statistical analysis

Data are expressed as mean ± SEM. The significance of differences between groups was evaluated by ANOVA, followed by Duncan’s multiple-range test. The criterion for statistical significance was P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Concentrations of vitreous hHGF

Concentrations of vitreous hHGF ranged from 0.01–3.06 ng/mL in nondiabetic control subjects, 1.10–7.38 ng/mL in nondiabetic subjects with proliferative vitreoretinopathy, 0.36–2.38 ng/mL in diabetic subjects without PDR, and 1.64–18.62 ng/mL in diabetic subjects with PDR. The mean vitreous hHGF concentration was significantly higher in diabetic subjects with PDR (5.70 ± 0.68 ng/mL, n = 33) than in nondiabetic control subjects (1.50 ± 0.20 ng/mL, n = 18, P < 0.01), nondiabetic subjects with proliferative vitreoretinopathy (3.31 ± 0.57 ng//mL, n = 10, P < 0.05), or diabetic subjects without PDR (1.29 ± 0.28 ng/mL, n = 8, P < 0.01). The mean vitreous hHGF concentration in nondiabetic subjects with proliferative vitreoretinopathy tended to be higher than in nondiabetic control subjects (P < 0.1). No significant correlation was found between age and vitreous hHGF concentrations in nondiabetic subjects with proliferative vitreoretinopathy (r = 0.089, P = 0.807, n = 10) or in diabetic patients with PDR (r = 0.131, P = 0.469, n = 33) or without PDR (r = 0.488, P = 0.219, n = 8); however, a weak positive correlation was found between age and vitreous hHGF concentrations in nondiabetic control subjects (r = 0.478, P = 0.045, n = 18). No correlation was found between serum glycosylated hemoglobin A1c values and vitreous hHGF concentrations in diabetic subjects with PDR (r = 0.007, P = 0.970, n = 33) or without PDR (r = 0.044, P = 0.918, n = 8).

Vitreous hHGF and neovascularization

PDR subjects with iridal neovascularization showed a higher mean vitreous hHGF concentration than those without iridal neovascularization [7.33 ± 1.16 ng/mL (n = 14) vs. 4.49 ± 0.72 ng/mL (n = 19), P < 0.05] (Fig. 1). In addition, the mean vitreous hHGF concentration was higher in PDR subjects with retinal neovascularization at the optic disc than in those with neovascularization elsewhere (Table 1). The mean vitreous hHGF concentration in the PDR group tended to be higher in the subjects with vitreous hemorrhage than in those without vitreous hemorrhage [6.33 ± 0.80 ng/mL (n = 26) vs. 3.36 ± 0.66 ng/mL (n = 7), P < 0.1]. The vitreous hHGF concentrations of PDR subjects did not differ with changes in the area of fibrous proliferative legions or the extent of previous retinal photocoagulation (Table 1).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have shown in this study that the mean hHGF concentration in the vitreous is higher in diabetic subjects with PDR than in either nondiabetic subjects or diabetic subjects without PDR. The vitreous hHGF concentration in diabetic subjects without PDR was almost the same as in nondiabetic control subjects and was much lower than that in PDR subjects; these findings indicate that the increase in vitreous hHGF in PDR subjects is not merely associated with diabetes mellitus. The major difference between the ocular lesions of PDR patients and those of other subjects is the presence of retinal neovascularization. Therefore, the results in the present study suggest that increased vitreous hHGF is involved in retinal neovascularization in PDR.

Capillary nonperfusion precedes the development of new vessels in the retina; it is the ischemic retina itself that triggers the angiogenic response (20, 21). The degree of capillary nonperfusion, as quantified by fluorescent angiography, is correlated with the likelihood of developing neovascularization in diabetic subjects (20). The angiogenic factors produced by the retina are likely to be diffusible, because extensive capillary nonperfusion in the retina is associated with iridal neovascularization (21). Therefore, the presence of neovascularization of the iris suggests not only retinal ischemia but also the presence of developing neovascularization in the retina. In the present study, PDR subjects with iridal neovascularization showed higher vitreous hHGF concentrations than those without. In addition, the mean vitreous hHGF concentration was higher in the PDR subjects with retinal neovascularization at the optic disc than in those with retinal neovascularization along the vascular arcade. The presence of neovascularization at the optic disc indicates a greater degree of retinal ischemia and development of retinal neovascularization than does neovascularization elsewhere (21). Furthermore, vitreous hHGF concentrations tended to be higher in PDR subjects with vitreous hemorrhage, which is frequently associated with retinal neovascularization, than in those without vitreous hemorrhage. These findings support the hypothesis that retinal ischemia elicits increases in vitreous hHGF concentration and that increased hHGF participates in retinal neovascularization in PDR.

The mean vitreous hHGF concentrations seen in this study were approximately 27-fold higher than the reported mean serum hHGF concentration of 0.213 ± 0.025 ng/mL in PDR subjects (22), and 14-fold higher than the reported mean serum hHGF concentration of 0.111 ± 0.009 ng/mL in nondiabetic control subjects (23). These data strongly indicate that vitreous hHGF does not represent leakage from serum to the vitreous, but rather that hHGF is produced endogenously in the human eye. The concentration of hHGF found in the vitreous is within the range previously shown to cause endothelial cell proliferation; concentrations of hHGF ranging from 1–10 ng/mL are enough to stimulate DNA synthesis in human aortic endothelial cells (24), and hHGF at concentrations between 1 and 5 ng/mL elicits proliferation of human endothelial cells in a dose-dependent manner (17). Therefore, increased vitreous hHGF is likely to play a role in retinal neovascularization.

The mean vitreous hHGF concentration in nondiabetic subjects with proliferative vitreoretinopathy tended to be higher than in control subjects. This indicates that vitreous hHGF may participate in fibrous proliferation in the retina and vitreous. However, vitreous hHGF concentrations in PDR subjects did not differ with changes in the area of fibrous proliferative change or the extent of previous photocoagulation, which is thought to induce fibrous retinal changes. Thus, vitreous hHGF may be partly involved in fibrous proliferative changes in proliferative vitreoretinopathy but is presumed not to make a significant contribution to fibrous proliferative lesions in PDR.

Vitreous hHGF concentrations observed in the subjects with PDR overlapped those in subjects without PDR, although the mean hHGF concentrations were statistically different between the two groups. The precise reason for this overlap is not clear from this study. It is possible that vitreous TGF-ß [which inhibits local hHGF production (25, 26, 27, 28)] or hHGF activator [which changes inactive hHGF to an active form (29)] may affect vitreous concentrations of hHGF. Further investigation is needed to clarify this point.

Intraocular concentrations of VEGF are reported to be increased in PDR subjects (5, 6). This growth factor, which is present in human retinal pigment epithelium, has a potent angiogenic action; and increased VEGF is expected to be involved in neovascularization in PDR. hHGF also has an angiogenic action, as well as endothelium-specific growth action, as described above. The stimulatory effect of hHGF on endothelial proliferation is thought to be caused by the same mechanism of intracellular signal transduction as that induced by VEGF, and this effect of hHGF is reported to be stronger than that of VEGF (24). This finding supports the idea that vitreous hHGF may be involved in retinal neovascularization in PDR, probably together with VEGF.

In an earlier study, we showed that the mean serum hHGF concentration is higher in PDR subjects than in other diabetic subjects without PDR (22). Although we did not measure serum hHGF concentrations in the present study, increased vitreous concentrations of hHGF might affect the serum hHGF concentration in PDR subjects, because the vitreous hHGF concentration is much higher than the serum concentration, as described above. Further investigation is needed to clarify this.

This is the first report to suggest that vitreous hHGF is involved in retinal neovascularization, as well as in the occurrence of vitreous hemorrhage in diabetic patients with PDR. Retinal ischemia may increase intraocular synthesis of hHGF in subjects with PDR. Vitreous hHGF is likely to be a key factor regulating retinal neovascularization in PDR.

	Acknowledgments

 
The authors thank Donald G. Puro, M.D., Ph.D., for his comments on the manuscript.

	Footnotes

 
¹ This study was supported, in part, by the Japanese Ministry of Education, Culture and Science (Research Grants 06454500 and 06771529), the Kyoto Foundation for the Promotion of Medical Science, and the USPHS.

Received July 8, 1998.

Revised September 21, 1998.

Accepted October 26, 1998.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nishimura, M. Articles by Yoshimura, M. Search for Related Content PubMed PubMed Citation Articles by Nishimura, M. Articles by Yoshimura, M.