Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

is relieved by oxygen from the newly formed vessels, VEGF mRNA expression is suppressed, moving the wave forward.

Supplemental oxygen interferes with normal retinal vascular development through suppression of VEGF mRNA (Figure 1). Furthermore, hyperoxia-induced vaso-obliteration is caused by apoptosis of vascular endothelial cells, and vaso-obliteration can be at least partially prevented by administration of exogenous VEGF18,19 and more specifically by placental growth factor-1 (PlGF-1), the specific agonist of VEGF receptor-1 (VEGFR- 1).20 This indicates that VEGFR-1 is required for maintenance of the immature retinal vasculature and explains at least in part the effect of hyperoxia on normal vessel development in ROP.

Ni vessel growth in retina

↓VEGF

Resolution of VEGF

Figure 7-1. Onset of neovascularization in the retinas of premature infants. In utero (a), the infant is exposed to low oxygen, but upon premature birth (b), a state of relative hyperoxia is induced with exposure to room air or supplemental oxygen. In addition, preterm birth is associated with very low levels of IGF-1 due to loss from the placenta and inability to overcome this loss due to an immature liver. This causes blood vessel formation to stop, resulting in local areas of hypoxia (c). The biological response is then to promote neovascularization (d), in part by increasing the expression of VEGF. IGF-1 rises slowly from low levels after preterm birth so that VEGF can then activate Akt and MAPK.

4.GH/IGF-1 IN PHASE II OF ROP

Although VEGF has an important role in the development of retinal blood vessels, it is clear that other biochemical mediators are also involved in the pathogenesis of ROP. Inhibition of VEGF does not completely inhibit hypoxia-induced retinal neovascularization in the second phase of ROP. Also, despite controlled use of supplemental oxygen, the disease persists as infants of ever lower gestational age are saved, suggesting that other factors

related to prematurity itself and growth and development are also at work. Because growth hormone (GH) has been implicated in proliferative diabetic retinopathy,21 we considered both GH and insulin-like growth factor 1 (IGF- 1), which mediates many of the mitogenic aspects of GH, as potential candidates for these factors.

In transgenic mice expressing a GH receptor antagonist or in normal mice treated with a somatostatin analog that decreases GH release, there is a substantial reduction in the amount of proliferative retinopathy, the second phase of ROP.22 The effect of GH inhibition is mediated through an inhibition of IGF-1, because administration of exogenous IGF-1 completely restores the neovascularization seen in the control mice. The GH/IGF-1 inhibition occurs without diminishing hypoxia-induced VEGF production. Proof of the direct role of IGF-1 in the proliferative phase of ROP in mice was established with an IGF-1 receptor antagonist, which suppressed retinal neovascularization without altering the vigorous VEGF response induced in the mouse ROP model.23

IGF-1 regulation of retinal neovascularization is mediated at least in part through control of VEGF activation of p44/42 MAPK. IGF-1 acts permissively to allow maximum VEGF induction of new vessel growth. Inadequate levels of IGF-1 inhibit vessel growth despite the presence of VEGF (Figure 2).

Figure 7-2. The relationship between IGF-1 and VEGF and its effect of the growth of new blood vessels.

5.LOW LEVELS OF IGF-1 AND PHASE I OF ROP

IGF-1 is also critical to the first phase of ROP24 and to the normal development of the retinal vessels. After birth, IGF-1 is not maintained at in utero levels due to the loss of IGF-1 provided by the placenta and the amniotic fluid. We hypothesized that IGF-1 is critical to normal retinal vascular development and that a lack of IGF-1 in the early neonatal period is associated with a lack of vascular growth and with subsequent proliferative ROP. To determine if IGF-1 is critical to normal blood vessel growth, retinal blood vessel development was examined in IGF-1 null mice. The retinal blood vessels grew more slowly in the IGF-1 null mice than in normal mice, a pattern very similar to that seen in premature babies with ROP. It was determined that IGF-1 controls maximum VEGF activation of the Akt endothelial cell survival pathway. This finding explains how loss of IGF-1 could cause ROP by preventing the normal survival of vascular endothelial cells.

These findings were confirmed in premature infants, where the mean

IGF-1 was significantly lower in babies with ROP than babies without ROP.24,25 These results suggest that replacement of IGF-1 to uterine levels

might prevent ROP by allowing normal retinal vascular development. If phase I is aborted, the destructive second phase of vaso-proliferation will not occur.

6.IGF-1 IN DIABETIC RETINOPATHY

6.1Elevated IGF-1 levels

There is a long-standing (and complex) association between IGF-1 and diabetic retinopathy,26-28 with conflicting evidence that elevated levels of serum IGF-1 are associated with proliferative retinopathy (phase II). The hypothesis that elevated levels of IGF-1 cause proliferative retinopathy is based in part on observations that patients with neovascular disease have very high vitreous levels of IGF-1.29-33 IGF system components could accumulate in the vitreous because of local production.34 However, it is thought that diffusion from serum plays an important role,35 and it has been suggested that increased levels of IGF-1 in the vitreous are the result and not the cause of neovascularization. This is based on the well-established increased permeability of the blood–retina barrier in diabetic patients. Circulating IGF and IGF binding protein-3 (IGFBP-3) levels are 10–100 times higher than those measured in vitreous.35 Furthermore, patients with

proliferative diabetic retinopathy show a significant positive correlation between serum and vitreous levels of IGF-1,36 and the increase in vitreous levels of IGF-1, IGF-2, and IGFBP-3 parallels the increase in vitreous of liver-derived serum proteins. Thus, it is generally accepted that diffusion from serum plays a key role. This accumulation is caused by a non-specific increase in leakiness of the blood-retina barrier, since these same elevations are found in patients with non-diabetic causes of leaky retinal vasculature.31,35

Some longitudinal studies have shown that intensive insulin treatment in patients with poorly controlled hyperglycemia, which rapidly increases total serum IGF-1, is associated with accelerated diabetic retinopathy.37,38 However, the majority of investigations (cross-sectional as well as longitudinal) have found no significant correlation between circulating IGF- 1 and the development of proliferative diabetic retinopathy.39-43 An animal study of normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 through an insulin promoter at supra-physiological levels in the retina developed loss of pericytes and thickening of basement membrane of retinal capillaries.44 In older transgenic mice over-expressing IGF-1, neovascularization of the retina and vitreous cavity were observed which was consistent with increased IGF-1 induction of VEGF expression45 in retinal cells. VEGF alone can cause these same effects.46 These accumulated findings suggest that once proliferative neovascular (and therefore leaky) vessels occur in the retina in phase II, leaked serum IGF-1 may further promote the proliferation of retinal vessels through stimulation of VEGF. However, it has not been established that serum IGF-1 in the absence of leaky vessels causes proliferative disease. In diabetic patients with acromegaly and elevated IGF-1 in serum and in vitreous, proliferative diabetic retinopathy is rare.47

6.2Low IGF-1 levels

Although less attention has been paid to the study of the first phase of diabetic retinopathy, there is evidence that low IGF-1 is associated with vessel loss (phase I), which could then lead to phase II, proliferative retinopathy. There is a substantial body of work indicating that low IGF-1 is associated with the hyperglycemia of poorly controlled diabetes, which is in turn the strongest risk factor for diabetic complications. Hyperglycemia is associated with elevated GH secretion and reduced serum IGF-1 concentrations.48,49 Low portal insulin levels are thought to lead to decreased production of IGF-1 with subsequently increased GH and IGFBP-1 levels.50 The elevation in GH secretion, due to loss of feedback inhibition of IGF-1 as a result of the low portal insulin levels, may worsen hyperglycemia by

counteracting insulin action.51 Thus, restoration of normal IGF-1 levels in insulin-treated patients with recombinant human (rh) IGF-1 or IGF- 1/IGFBP-3 complex results in a concomitant reduction in GH secretion and insulin requirement to maintain euglycemia.52-55

A study in Laron dwarfs with diabetes and with very low levels of IGF-1 indicates that these patients undergo phase I and phase II of diabetic retinopathy, suggesting that low IGF-1 may be an important contributing factor to retinopathy.56 Low IGF-1 may also be involved in large vessel disease. Individuals with low circulating IGF-1 levels and high IGFBP-3 levels have a significantly increased risk of developing ischemic heart disease during a 15-year follow-up period.57 More recent evidence suggests that very low IGF-1 directly causes decreased vascular density.58

This accumulated evidence indicates that low IGF-1 is associated with vessel loss and may be detrimental in diabetes by contributing to early vessel degeneration in phase I. This vaso-obliteration sets the stage for hypoxia, leading later to neovascularization/proliferative retinopathy. Thus, treatment of diabetic patients with IGF-1 within the normal physiological range as an adjunct to insulin might prevent and not worsen the development of diabetic microvascular complications.59

7.CLINICAL IMPLICATIONS

These studies suggest a number of ways to intervene medically in the development of retinopathy, but they also make clear that timing is critical to any intervention. Inhibition of either VEGF or IGF-1 early after birth can prevent normal blood vessel growth and precipitate ROP, whereas inhibition at the second neovascular phase might prevent destructive neovascularization. This also may be true in diabetic retinopathy. The choice of any intervention must be made to promote normal physiological development and survival of both blood vessels and other tissue. In particular, the proof that development of ROP is associated with low levels of IGF-1 after premature birth suggests that physiological replacement of IGF-1 to levels found in utero might prevent ROP by allowing normal vascular development.

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Chapter 8

HYPOXIA AND RETINAL

NEOVASCULARIZATION

Bruce A. Berkowitz

Departments of Anatomy and Cell Biology and Ophthalmology, Wayne State University, Detroit, Michigan

1.INTRODUCTION

Normally, retinal vessels develop in utero by two mechanisms: vasculogenesis (formation of vessels from precursor cells) and angiogenesis (sprouting of vessels from the existing circulation). The inner (or superficial) circulation develops first, largely via vasculogenesis, and covers the retina by about week 26 post-conception. Outer (or deep net) vessel development lags behind that of the inner circulation and is mostly complete by birth. Under special circumstances, a third form of new retinal vessel growth also occurs. In this case, poorly formed blood vessels abnormally grow from the

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