Endothelial Cell Hypertrophy Induced by Vascular Endothelial Growth Factor in the Retina

Hofman, P; Blijswijk, B. C. van; Gaillard, Pieter J.; Vrensen, Gijs F.J.M.; Schlingemann, R.O.

doi:10.1001/archopht.119.6.861

Cited by 81 publications

(59 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…57 In addition, VEGF can induce hypertrophy of endothelial cells of retinal capillaries, at the expense of lumen diameter. 57,58 We provide evidence for an increase in VEGF in the retinas of Atm Ϫ/Ϫ mice. This can account for the vasoconstriction and vascular leakage that we found in the retinas of Atm Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 71%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

show abstract

Section: Discussionmentioning

confidence: 71%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…9 Briefly, eyes were perfused with 4% paraformaldehyde intracardiacly and then eyes were enucleated. A corneal puncture was made and eyes were put into 4% paraformaldehyde for 48 h. Immunohistochemical staining was performed on formalin-fixed, parafinembedded tissue by using the streptavidin-biotin method and 4-5 sections were obtained for evaluation from each eye.…”

Section: Retinal Biochemical Analysismentioning

confidence: 99%

Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats

Özdemir

Ergün

Bakarış

et al. 2014

Eye

View full text Add to dashboard Cite

Purpose To evaluate the role of melatonin, an antioxidant agent, in diabetic oxidative stress and vascular damage. Methods Diabetes was induced in 21 male Wistar rats by intraperitoneal (IP) administration of streptozotocin and then the rats were equally and randomly allocated to diabetic, melatonin, and vehicle groups. Seven healthy normal rats with similar features comprised the control group as the fourth group. All animals were followed for 12 weeks. The melatonin group received IP melatonin daily and the vehicle group received 2.5% ethanol IP at the last month. At the end of 12 weeks, the rats were killed and retinas were harvested. The retinas were investigated for the existence of hypoxiainducible factor 1-a (HIF-1a), vascular endothelial growth factor A (VEGF-A), and pigment epithelium-derived factor (PEDF) by ELISA. Retinal oxidative stress is quantitated by measuring nitrotyrosine and malondialdehyde levels. Retinal immunohistochemistry with antibody against CD31 antigen was carried out on retinal cross-sections. For statistics, ANOVA test was used for multiple comparisons. Results Hyperglycemia increased retinal oxidation as measured through levels of nitrotyrosine and malondialdehyde. Diabetic retinas are also associated with abnormal vascular changes such as dilatation and deformation. HIF-1a, VEGF-A, and PEDF were all increased because of diabetic injury. Melatonin showed a potential beneficial effect on retinopathy in diabetic rats. It decreased retinal nitrotyrosine and malondialdehyde levels, showing an antioxidative support. The vasculomodulator cytokines are decreased accordingly by melatonin therapy. Melatonin normalized retinal vascular changes as well. ConclusionMelatonin may show some advantage on diabetic vascular changes through decreasing oxidative stress and vessel-related cytokines.

show abstract

“…Increased levels of VEGF have been identified in models of retinal ischemia by us and others (21,43). Hypoxia induces significant increases in VEGF expression in cells of the ganglion cell layer of the inner retina, and this increment would promote angiogenesis (43).…”

mentioning

confidence: 96%

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Rey-Funes

Larráyoz

Fernández

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

-Perinatal asphyxia induces retinal lesions, generating ischemic proliferative retinopathy, which may result in blindness. Previously, we showed that the nitrergic system was involved in the physiopathology of perinatal asphyxia. Here we analyze the application of methylene blue, a well-known soluble guanylate cyclase inhibitor, as a therapeutic strategy to prevent retinopathy. Male rats (n ϭ 28 per group) were treated in different ways: 1) control group comprised born-to-term animals; 2) methylene blue group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery; 3) perinatal asphyxia (PA) group comprised rats exposed to perinatal asphyxia (20 min at 37°C); and 4) methylene blue-PA group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery, and then the pups were subjected to PA as above. For molecular studies, mRNA was obtained at different times after asphyxia, and tissue was collected at 30 days for morphological and biochemical analysis. Perinatal asphyxia produced significant gliosis, angiogenesis, and thickening of the inner retina. Methylene blue treatment reduced these parameters. Perinatal asphyxia resulted in a significant elevation of the nitrergic system as shown by NO synthase (NOS) activity assays, Western blotting, and (immuno)histochemistry for the neuronal isoform of NOS and NADPH-diaphorase activity. All these parameters were also normalized by the treatment. In addition, methylene blue induced the upregulation of the anti-angiogenic peptide, pigment epithelium-derived factor. Application of methylene blue reduced morphological and biochemical parameters of retinopathy. This finding suggests the use of methylene blue as a new treatment to prevent or decrease retinal damage in the context of ischemic proliferative retinopathy. retina; nitric oxide; ischemic proliferative retinopathy; methylene blue; angiogenesis PERINATAL ASPHYXIA (PA) is one of the most severe problems in perinatology services across the world (9,15,23,27). PA generates a transient global hypoxia-ischemia status that damages the brain, spinal cord, and retina (14, 17, 39, 52). The degree and the length of perinatal asphyxia are decisive for the development of injury sequelae, such as attention-deficit hyperactivity disorder (1), epilepsy, mental retardation, spasticity, and visual or hearing alterations (61). One third of asphyctic neonates develop serious long-term neurological injuries including several degrees of ischemic proliferative retinopathy (IPR) and even blindness (20).In rats, the retina is particularly sensitive to oxygen alterations (56), and the morphological changes observed in its inner layers are compatible with some alterations observed in human diseases such as retinopathy in diabetes, retinal vein occlusion, and retinopathy of prematurity (ROP), an avoidable cause of visual impairment and blindness in children (20, 61). The changes observed in asphyctic animals include ganglion cell degeneration, n...

show abstract

Endothelial Cell Hypertrophy Induced by Vascular Endothelial Growth Factor in the Retina

Cited by 81 publications

References 24 publications

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Contact Info

Product

Resources

About