Modulation of Thrombospondin 1 and Pigment Epithelium–Derived Factor Levels in Vitreous Fluid of Patients With Diabetes

Wang, Shoujian; Gottlieb, Justin L.; Sorenson, Christine M.; Sheibani, Nader

doi:10.1001/archophthalmol.2009.53

Cited by 41 publications

(36 citation statements)

References 39 publications

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“…We previously showed that TSP1 is a modulator of ocular vascular homeostasis and its expression is essential for appropriate remodeling and maturation of retinal vasculature. 10,15,[24][25][26] The retinal vascular density was increased in TSP1…”

Section: Discussionmentioning

confidence: 98%

Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization

Fei

Palenski

Wang

et al. 2015

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To determine thrombospondin-2 (TSP2) expression and its impact on postnatal retinal vascular development and retinal neovascularization. Methods: The TSP2-deficient (TSP2 -/ -) mice and a line of TSP2 reporter mice were used to assess the expression of TSP2 during postnatal retinal vascular development and neovascularization. The postnatal retinal vascularization was evaluated using immunostaining of wholemount retinas prepared at different postnatal days by collagen IV staining and/or TSP2 promoter driven green fluorescent protein (GFP) expression. The organization of astrocytes was evaluated by glial fibrillary acidic protein (GFAP) staining. Retinal vascular densities were determined using trypsin digestion preparation of wholemount retinas at 3-and 6-weeks of age. Retinal neovascularization was assessed during the oxygen-induced ischemic retinopathy (OIR). Choroidal neovascularization (CNV) was assessed using laser-induced CNV. Results: Using the TSP2-GFP reporter mice, we observed significant expression of TSP2 mRNA in retinas of postnatal day 5 (P5) mice, which increased by P7 and remained high up to P42. Similar results were observed in retinal wholemount preparations, and western blotting for GFP with the highest level of GFP was observed at P21. In contrast to high level of mRNA at P42, the GFP fluorescence or protein level was dramatically downregulated. The primary retinal vasculature developed at a faster rate in TSP2-/ -mice compared with TSP2 + / + mice up to P5. However, the developing retinal vasculature in TSP2 + / + mice caught up with that of TSP2 -/ -mice after P7. No significant differences in retinal vascular density were observed at 3-or 6-weeks of age. TSP2-/ -mice also exhibited a similar sensitivity to the hyperoxia-mediated vessel obliteration and similar level of neovascularization during OIR as TSP2 + / + mice. Lack of TSP2 expression minimally affected laserinduced CNV compared with TSP2 + / + mice. Conclusions: Lack of TSP2 expression was associated with enhanced retinal vascularization during early postnatal days but not at late postnatal times, and minimally affected retinal and CNV. However, the utility of TSP2 as a potential therapeutic target for inhibition of ocular neovascularization awaits further investigation.

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Section: Discussionmentioning

confidence: 98%

Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization

Fei

Palenski

Wang

et al. 2015

Journal of Ocular Pharmacology and Therapeutics

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“…factor (VEGF), thrombospondin-1 (TSP1), and pigment epithelium-derived factor (PEDF) (23,35,46). However, the contribution of these factors to regulation of lung vascular homeostasis and pathologies remains poorly understood.…”

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confidence: 99%

“…Alterations in this coordinated activity and dysfunction in the regulation of VEGF and PEDF expression have been implicated in pathogenesis of various diseases with a neovascular component, including age-related macular degeneration, diabetic retinopathy, and cancer. These alterations have been generally associated with increased expression of VEGF, while that of PEDF is suppressed (1,46), favoring a proangiogenic and inflammatory state. However, the contribution of such alterations to various lung pathologies requires further investigation.…”

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confidence: 99%

PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium

Shin

Sorenson

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pigment epithelium-derived factor (PEDF) is a multifunctional protein with important roles in regulation of inflammation and angiogenesis. It is produced by various cell types, including endothelial cells (EC). However, the cell autonomous impact of PEDF on EC function needs further investigation. Lung EC prepared from PEDF-deficient (PEDF-/-) mice were more migratory and failed to undergo capillary morphogenesis in Matrigel compared with wild type (PEDF+/+) EC. Although no significant differences were observed in the rates of apoptosis in PEDF-/- EC compared with PEDF+/+ cells under basal or stress conditions, PEDF-/- EC proliferated at a slower rate. PEDF-/- EC also expressed increased levels of proinflammatory markers, including vascular endothelial growth factor, inducible nitric oxide synthase, vascular cell adhesion molecule-1, as well as altered cellular junctional organization, and nuclear localization of β-catenin. The PEDF-/- EC were also more adhesive, expressed decreased levels of thrombospondin-2, tenascin-C, and osteopontin, and increased fibronectin. Furthermore, we showed lungs from PEDF-/- mice exhibited increased expression of macrophage marker F4/80, along with increased thickness of the vascular walls, consistent with a proinflammatory phenotype. Together, our data suggest that the PEDF expression makes significant contribution to modulation of the inflammatory and angiogenic phenotype of the lung endothelium.

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“…30 In patients with diabetic retinopathy, TSP-1 is routinely low in the vitreous fluid; thus, TSP-1 plays a role in the alterations in the angiogenic balance of the eye. 41 Attenuation of proliferation and migration of retinal pericytes is seen in TSP-1-deficient mice. In addition, AMD patients express decreased levels of TSP-1 in Bruch's membrane and choriocapillaris, which may result in a permissive environment for choroidal neovascularization (CNV).…”

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confidence: 99%

Thrombospondin-1-Based Antiangiogenic Therapy

Sims

Lawler

2015

Journal of Ocular Pharmacology and Therapeutics

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Ocular angiogenesis is one of the underlying causes of blindness and vision impairment and may occur in a spectrum of disorders, including diabetic retinopathy, neovascular age-related macular degeneration, retinal artery or vein occlusion, and retinopathy of prematurity. As such, strategies to inhibit angiogenesis by suppressing vascular endothelial growth factor activity have proven to be effective in the clinic for the treatment of eye diseases. A complementary approach would be to increase the level of naturally occurring inhibitors of angiogenesis, such as thrombospondin (TSP)-1. This article summarizes the development of TSP-1-based inhibitors of angiogenesis.

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Modulation of Thrombospondin 1 and Pigment Epithelium–Derived Factor Levels in Vitreous Fluid of Patients With Diabetes

Cited by 41 publications

References 39 publications

Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization

Thrombospondin-2 Expression During Retinal Vascular Development and Neovascularization

PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium

Thrombospondin-1-Based Antiangiogenic Therapy

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