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IGF-I Is Critical for Normal Vascularization of the Human Retina

Department of Clinical Neurosciences (A.H.), Section of Ophthalmology, Department of Pediatrics (A.H., A.K., K.A.W.), International Pediatric Growth Research Centre, Department of Internal Medicine (B.C.), Research Center for Endocrinology and Metabolism, Sahlgrenska Academy of Göteborg University, S-416 85 Göteborg, Sweden; Mälarsjukhuset (K.S.), S-631 88 Eskilstuna, Sweden; Pediatric Endocrinology Unit (M.B., L.D.), Federal University of Parana, Curitiba 80430-040, Brazil; Department of Endocrinology (M.S.), Sankt Bartholomews, EC1A 7BE London, United Kingdom; Department of Biostatistics (E.S.), Örebro University, S-701 82 Örebro, Sweden; Harvard Medical School (L.S.), Boston, Massachusetts 02115; and Department of Ophthalmology (D.W.), Rabin Medical Center, Beilinson Campus, Unit of Endocrinology and Diabetes Research (Z.L.), Schneider Children’s Medical Center, Tel Aviv University, 49202 Tel Aviv, Israel

Address all correspondence and requests for reprints to: Ann Hellström, Section of Pediatric Ophthalmology, The Queen Silvia Children’s Hospital, Sahlgrenska Academy of Göteborg University, S-416 85 Göteborg, Sweden. E-mail: . ann.hellstrom{at}medfak.gu.se

Abstract

Experimental and clinical studies suggest that GH and IGF-I may be involved in neovascularization of the retina in diabetes and retinopathy of prematurity. However, the role of GH and IGF-I has not been well established in normal retinal vessel development in humans. Therefore, we examined retinal vessel morphology by digital image analysis of ocular fundus photographs in 13 patients with genetic defects of the GH/IGF-I axis and low levels of IGF-I during and after normal retinal vessel growth. Eleven patients (four females and seven males aged 10–49 yr) had defects of the GH receptor (Laron syndrome). One male (20 yr) had a partial deletion of the IGF-I gene, and one female (14 yr) had a single allele deletion of the IGF-I receptor gene. Patients with defects in the GH/IGF-I axis had significantly less retinal vascularization as evidenced by lower number of vascular branching points (median 23, range 16–25), compared with the reference group of 100 normal controls (median 28, range 19–40, P < 0.001). All 13 individuals had vascular branching points below the median of the reference group. This is the first study to provide genetic evidence for a role of the GH and IGF-I system in retinal vascularization in humans.

THERE HAS BEEN great interest in the mechanism of retinal neovascularization because it plays a critical role in retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration. Several decades ago it was reported that pituitary ablation resulted in remission of diabetic retinopathy (1, 2, 3) and the remission was related to the reduction in serum levels of GH (1). However, the specific role of GH in neovascularization has been controversial, and lately much attention has focused instead on angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor, and IGF-I and IGF-II (4, 5, 6). Early studies in cell culture suggested that IGF-I directly influences endothelial cell growth (4, 5, 6). Experiments in rodents have provided new evidence that IGF-I also influences angiogenesis and the development of retinal neovascularization through interaction with locally produced factors such as VEGF (7), acting as a permissive factor for maximum VEGF stimulation of angiogenesis (7, 8). Recently, it was also demonstrated that low IGF-I levels in serum is associated with ROP, which is associated with poor initial vascular development, indicating that IGF-I might be involved in human angiogenesis (7). In this study we provide the first genetic evidence for a role of the GH/IGF-I axis in normal retinal vascularization in humans.

Subjects and Materials

Study group

From 1998 to 2001, an extensive effort was made to obtain fundus photographs from individuals with genetic defects of the GH/IGF-I axis. The 13 individuals below were recruited for the present study.

Two children with Laron syndrome (9) had an ophthalmological examination in Sweden.

Eight individuals with Laron syndrome were investigated in Israel. In addition, one male (20 yr) with Laron syndrome and one male (20 yr) with partial deletion of the IGF-I gene (10) had an ophthalmological examination performed in Great Britain. One girl (14 yr) with single-allele deletion of the IGF-I receptor gene (11) was investigated in Brazil.

Thus, 13 (5 females and 8 males aged 10–49 yr) full-term individuals were included. One girl with single-allele deletion of the IGF-I receptor gene was treated for 16 months with a mean dose of recombinant human GH of 0.95 IU/kg per week. One boy with partial deletion of the IGF-I gene was treated for 19 months with a mean dose of recombinant human IGF-I (rhIGF-I) of 80 µg/kg daily. One girl with Laron syndrome had received rhIGF-I therapy (180 µg/kg daily) for 7 yr, and two boys with Laron syndrome had received rhIGF-I treatment for 5 yr (120 µg/kg twice daily). All of these individuals had their fundus photographed, after or during GH/IGF-I-treatment. All individuals were below -3 SD height. All had IGF-I replacement therapy starting after age 2.5 yr when retinal vascular development is complete.

Reference group

One hundred healthy individuals (56 boys and 44 girls) born at term, with an age range of 3–20 yr, constituted a reference group for evaluation of ocular fundus morphology. Detailed data for these children and adolescents are presented elsewhere (12). In addition, the evaluation of fundus photographs of 20 healthy individuals between 20 and 50 yr of age were included to match the patients’ ages.

Methods

All individuals had an eye examination, including fundus photography after cycloplegia. Visual acuity ranged from 20/40 to 20/20 (median 20/20). Refraction ranged from -1.5 to +2.0 diopters. All fundus photographs were evaluated without knowledge of IGF-I status by quantitative analysis of fundus morphology, using a computer-assisted digital mapping system (13). Only well-focused photographs, with the optic disc well centered (within half a disc size off center) were accepted. The original color transparency was projected simultaneously with the personal computer monitor image to facilitate definition of the different fundus structures of the scanned fundus photograph.

The retinal vascularization was analyzed with respect to number of branching points and tortuosity of arteries and veins. Measurements of the retinal vessels arterioles and venules (referred to as arteries and veins) were made by tracing each vessel (path length) from its origin on the optic disc to a reference circle with a radius of 3.0 mm from the geometric center of the optic disc. The index of tortuosity for arteries and veins was defined as the path length of the vessel divided by the linear distance from the vessel origin to the reference circle. The number of vessel branching points within the reference circle was automatically calculated. Arteries were distinguished from veins by their smaller caliber and brighter appearance.

The fundus photographs from both eyes of an individual were evaluated, and the mean of the measurements represented the individual. The comparison with the reference group was performed by means of the Wilcoxon Mann-Whitney U test.

Informed consent was obtained from the children and parents and, if old enough, from the patients themselves.

Results

Patients with defects in GH/IGF-I axis had significantly lower number of vascular branching points (median 23, range 16–25), compared with the reference group (12) of 100 normal controls (median 28, range 19–40, P < 0.001) (Figs. 1 and 2). All 13 individuals had vascular branching points below the median of the reference group.

View larger version (11K): [in this window] [in a new window]   Figure 1. Number of retinal vascular branching points in individuals with defects in the GH ( n = 11), IGF-I (• n = 1), or IGF-I receptor genes (• n = 1). The shaded area depicts the 10th to the 90th centile range, and the center line indicates the median for the healthy reference group of 100 controls aged 2–20 yr (9 ). The lines represents the minimum (dotted line), the median (dashed line), and the maximum (dotted line) of 20 healthy individuals aged 20–50 yr.

View larger version (60K): [in this window] [in a new window]   Figure 2. Reduced retinal vascularization in an 11-yr-old girl with Laron syndrome (a) and normal vascularization in an 11-yr-old girl control (b).

IGF-I or GH administration to the three patients with Laron syndrome and to the two patients with IGF-I gene abnormalities did not affect the abnormal findings in the retinal vascularization (Fig. 1).

Discussion

In the present study, we found abnormal retinal vessel morphology in patients with genetic defects in the GH/IGF-I axis. GH may act by induction of the IGF-I system or directly through its receptor (14). All the patients studied have in common absent IGF-I activity starting in utero, when retinal vascularization begins. The patients with Laron syndrome have a GH receptor defect leading to high serum levels of GH without possible GH receptor signal transduction, and they therefore lack GH-induced IGF-I generation (9). Serum IGF-I is also obviously low in the patient with an IGF-I deletion in the presence of a functioning GH receptor (10), and the patients with the IGF-I receptor defect (11) have an impairment in IGF-I activity in the presence of normal GH levels and non-IGF-I-dependent action.

Considering the above, it must be concluded that the pathological findings in the retinal vascularization are likely owing to low IGF-I, not to GH deficiency.

This conclusion is supported by studies in mice that show that induced retinal neovascularization is inhibited when the GH receptor is inhibited, and subsequently the levels of IGF-I, are reduced. However, in the presence of GHR inhibition, the inhibition of neovascularization is completely reversed with exogenous IGF-I administration (15), illustrating the critical role of IGF-I.

We have found a strong association between reduced serum levels of IGF-I in preterm children and the development of ROP (7), a disease initiated by poor vascular development. Although low IGF-I correlates with proliferative retinopathy in ROP, we do not yet know whether low IGF-I causes the first phase of the disease, poor retinal growth, which leads to proliferative ROP. However, studies in cell culture support the idea that IGF-I is critical to vessel development (4, 5, 6). In retinal vascular endothelial cells, IGF-I above a threshold level is necessary for maximum VEGF activation of the MAPK and Akt pathways, important for endothelial cell proliferation and survival (7, 8). It may be speculated that premature infants with normal retinal vascularization, without ROP, have sufficiently high serum levels of IGF-I for maximum VEGF activation of the Akt pathway. On the other hand, lower serum levels of IGF-I in premature infants are associated with a markedly increased risk for development of ROP, which is related to initial poor vascular development and a large area of avascular retina.

VEGF is produced in the increasingly hypoxic avascular retina as metabolic demands increase with development, and as a result VEGF levels rise in the vitreous (16). In premature infants, who do not develop ROP, IGF-I rises quickly after birth. Thus, VEGF does not accumulate because vascular growth can occur, providing oxygen to the maturing retina (17, 18). When IGF-I remains low for an extended period, as in children developing ROP, vessels cease to grow, the maturing avascular retina becomes hypoxic, and VEGF accumulates. With increased postnatal growth and development, IGF-I rises to a threshold level with high levels of VEGF still present, and a rapid growth of new blood vessels (retinal neovascularization) is triggered.

In term children (such as the patients in this study), vessel growth is almost complete at birth, but remodeling continues for some time. All children in this study have genetic defects resulting in low IGF-I in utero when retinal vascularization occurs as well as postnatally when remodeling takes place. In these patients, low IGF-I may also have a similar effect in preventing maximum vessel growth and survival mediated through VEGF activation of Akt and MAPK and might account for the decreased vascular density seen in this study. What could be the consequences of the observed vascular abnormalities? There is reason to believe that the retinal vascular pattern noted in patients with genetic defects in the GH/IGF-I axis reflects similar changes in other vascular systems with similar architecture and developmental timing, i.e. the cerebral and coronary vessels and the vessels in the kidneys. Poor oxygenation could affect any organ function.

In the present study, four subjects with defects in the GH receptor or IGF-I gene received IGF-I treatment after retinal vascular development was complete without signs of neovascularization during treatment. Although the study group was small, and we do not know whether IGF-I levels achieved were still subnormal (or the IGF-I levels achieved were in the normal range), it may be speculated that an increase in serum IGF-I outside the critical developmental period does not appear to induce neovascularization. However, the situation may be different in subjects with diseases associated with neovascularization such as in diabetic neovascularization in which other angiogenic factors such as VEGF may also be expressed (19). Although further studies are required, this suggests that, in humans, IGF-I may act as a critical permissive factor for normal vascularization and neovascularization under circumstances when other angiogenic factors such as VEGF are expressed.

Footnotes

This work was supported by grants from The Swedish Medical Research Council (7509, 10863, 11331, 11576).

Abbreviations: rhIGF, Recombinant human IGF; ROP, retinopathy of prematurity; VEGF, vascular endothelial growth factor.

Received November 30, 2001.

Accepted March 21, 2002.

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