PEDF is a member of the serine protease inhibitor (serpin) superfamily with neurotrophic and antiangiogenic properties, and a decreased level of PEDF in the eye is important in the pathogenesis of proliferative DR40. In the retina, angiogenesis is regulated by two counterbalancing systems: angiogenic stimulators, such as VEGF, and angiogenic inhibitors, such as angiostatin and pigment epithelium-derived factor (PEDF)40.
PEDF is a natural extracellular component of the retina and has been found in the vitreous and aqueous humors. Decreased levels of PEDF were reported in the ocular fluids of patients with angiogenic eye diseases41. PEDF has potent antiangiogenic activity in retinal EC growth and migration and suppressed ischemia-induced retinal neovascularization42.
Pericyte loss is one of the earliest hallmarks of DR and an important reason for pericyte loss is reactive oxygen species (ROS) In DR, PEDF has a novel benefit since PEDF protects retinal pericytes against oxidative stress-induced injury through its anti-oxidative properties, which might slow the development of diabetic retinopathy43.PEDF protects against high glucose or ROS induced pericyte apoptosis and dysfunction through its anti-oxidative properties via induction of glutathione44.
Guoquan et al45 compared susceptibilities of Sprague Dawley(SD) and Brown Norway(BN) rats with ischemia-induced retinal neovascularization. They found that the hyperoxia-treated BN rats showed a significant reduction in retinal PEDF and a substantial increase of VEGF at both the protein and RNA levels, resulting in an increased VEGF-to-PEDF ratio. The results suggested that BN rats developed more severe retinal neovascularization, which correlated with a greater increase of the VEGF-to-PEDF ratio in BN than in SD rats45.
PEDF, a potent inhibitor of angiogenesis, has been found to be involved in the pathogenesis of PDR46, 47. It is well known that there are quite a few stimulators and inhibitors of angiogenesis in the eye; among them, VEGF has been identified as a primary angiogenic stimulator48 and PEDF as a major angiogenic inhibitor47. The time course of the VEGF-to-PEDF ratio change correlated with the development and progression of retinal neovascularization. The VEGF-to-PEDF ratio represented a dynamic balance between angiogenic stimulators and inhibitors; and disturbance of the balance played a key role in the pathogenesis of DR45, 49, 50. In vitro study revealed that lowering of the VEGF-to-PEDF mRNA ratio could inhibit the migration of uveal melanoma cells51.
Additionally, PEDF induces the ERK signal cascade which contributes to retinal pigment epithelial cell cytoprotection against oxidative stress52. Thus, retinal cells including the BRB capillaries and their supportive and protective pericytes may possess a system capable of efficiently responding to PEDF43' 44.
Retinal ischemia induces intraocular neovascularization,presumably by stimulating the expression of angiogenic growth factors and by inhibiting the release of antiangiogenic cytokines53, 54. Vitreal levels of angiogenic growth factors have been shown to be directly associated with the degree of retinal angiogenesis15, 55. PEDF protects cerebellar granule cells against neurotoxic agents56 and is also called early population doubling level cDNA-1 (EPC-
1), reflecting its upregulation during cell cycle arrest (G0) in young but not in senescent cultured fibroblasts57.
PEDF has been shown to be a highly effective inhibitor of angiogenesis in animal and cell culture models. The production of PEDF was decreased by hypoxia47, which is also a central pathogenic stimulus in PDR. Immunoneutralization of PEDF diminished the ability of cadaveric human vitreous to inhibit migration of endothelial cells, thereby demonstrating that a loss of PEDF is functionally important in mediating angiogenic properties of human vitreous ex vivo. Most importantly, systemically administered PEDF prevented aberrant blood vessel growth in a murine model of ischemia-induced retinopathy58.
PEDF has been shown to be a major antiangiogenic growth factor in the mammalian eye. Joachim41 et al analyzed the in vivo regulation of PEDF in patients with and without hypoxic eye disease. Their data strongly support the concept that retinal angiogenesis is induced by loss of the major angiogenesis inhibitor in the eye, PEDF, in combination with an increased expression of angiogenic growth factors such as VEGF. These findings suggest that substitution of angiogenesis inhibitors may be an effective approach in the treatment of PDR41.
In the study of Zhi59 et al ,diabetic rats and control animals were randomly assigned to receive perindopril or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without perindopril. The results showed the VEGF-to-PEDF ratio was increased in the retina of diabetic rats; perindopril lowered the increased VEGF-to-PEDF ratio in diabetic rats and ameliorated the retinal damage. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF-to-PEDF ratio by reducing mitochondrial ROS and the decreased ROS production was a result of perindopril induced upregulation of PPARY and UCP-2 expression59.
Although VEGF is the major factor in the initiation of advanced stages of diabetic retinopathy, it is increasingly recognized that PlGF is a significant factor in promoting the aberrant angiogenesis characteristic of a variety of pathological states.
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