PEDF expression affects retinal endothelial cell proangiogenic properties through alterations in cell adhesive mechanisms

Abstract

Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis. Although various ocular cell types including retinal endothelial cells (EC) produce PEDF, we know very little about cell autonomous effects of PEDF in these cell types. Here we determined how PEDF expression affects retinal EC proangiogenic properties. Retinal EC were prepared from wild-type (PEDF) and PEDF-deficient (PEDF) mice. The identity of EC was confirmed by staining for specific markers including vascular endothelial cadherin, CD31, and B4-lectin. Retinal EC also expressed VEGF receptor 1 and endoglin, as well as ICAM-1, ICAM-2, and VCAM-1. PEDF retinal EC were more proliferative, less apoptotic when challenged with HO less migratory, and less adherent compared with PEDF EC. These changes could be associated, at least in part, with increased levels of tenascin-C, fibronectin, thrombospondin-1 and collagen IV, and lower amounts of osteopontin. PEDF EC also exhibited alterations in expression of a number of integrins including α2, αv, β1, β8, and αvβ3, and cell-cell adhesion molecules including CD31, zonula occluden-1, and occludin. These observations correlated with attenuation of capillary morphogenesis and increased levels of oxidative stress in PEDF EC. PEDF EC also produced lower levels of VEGF compared with PEDF cells. Thus, PEDF deficiency has a significant impact on retinal EC adhesion and migration, perhaps through altered production of extracellular matrix and junctional proteins in response to increased oxidative stress affecting their proangiogenic activity.

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

“…Thbs1-deficient ChEC were less migratory compared with wild type cells ( Wang et al, 2006 ; Fei et al, 2014 ). Thus, the decreased Thbs1 expression in ChEC is consistent with their reduced migration in the presence of caffeine ( Wang et al, 2006 ; Fei et al, 2014 ; Falero-Perez et al, 2017 ; Farnoodian et al, 2018 ).…”

Preclinical Evaluation of a Cell-Based Gene Therapy Using the Sleeping Beauty Transposon System in Choroidal Neovascularization

“…Because reduction of PEDF levels is linked to the pathogenesis of neovascular AMD, PEDF treatment is beneficial to treat this degenerative disorder. Exogenously administered PEDF provides potent antiangiogenic activity by directly inhibiting proliferation of endothelial cells and/or inducing their death through both extrinsic and intrinsic apoptotic pathways 1 , 2 , 19 . PEDF has demonstrated to have anti-inflammatory properties, by decreasing the expression of pro-inflammatory factors such as the tumor necrosis factor-α (TNF-α) as shown in a rat model of retinopathy 20 .…”

Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes

“…Second, increased levels of VEGF were found in the vitreous body fluid of patients with proliferative diabetic retinopathy (PDR), and differences in VEGF concentration were found between patients with PDR and non-proliferative diabetic retinopathy (NPDR) [ 107 ]. Altogether, the level of VEGF in the vitreous body fluid may reflect the progression of DR, suggesting the potential of VEGF as a biomarker [ 56 , 57 ].…”

“…Microvascular dysfunction of endothelial cells in retina, which results from oxidative stress and inflammation in the course of diabetes, can be restored with exogenous PEDF [ 58 ]. Serum levels of PEDF are elevated in type 1 and 2 DM, but with no specific link to DR [ 57 ]. On the contrary, PEDF concentration was decreased in the vitreous body fluid of diabetic patients with DR, compared to diabetic patients without retinopathy [ 52 ].…”

“…Consequently, the concentration of homocysteine is increased both in plasma and in the vitreous body in DR compared to healthy controls [ 76 , 121 ]. In addition, differences between plasma levels of homocysteine in diabetics with PDR, NPDR and diabetics without retinopathy were found, with the highest level in PDR compared to other groups [ 57 ]. Hyperhomocysteinemia is also associated with micro- and macrovascular changes, which could lead to nerve injury, and elevated levels of plasma homocysteine are an independent risk factor of diabetic neuropathy [ 78 ].…”