Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Joussen, Antonia M.; Murata, Toshinori; Tsujikawa, Akitaka; Kirchhof, Bernd; Bursell, Sven–Erik; Adamis, Anthony P.

doi:10.1016/s0002-9440(10)63952-1

Cited by 512 publications

(424 citation statements)

References 12 publications

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“…A diabetes-induced increase in leucostasis (leucocytes adhering to the luminal wall of the vasculature) has been postulated to contribute to endothelial cell death or dysfunction in the retina [25]. A significant increase in leucostasis was demonstrated in WT mice that had been diabetic for 3 months compared with their non-diabetic counterparts (p<0.05) (Fig.…”

Section: Resultsmentioning

confidence: 93%

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

et al. 2007

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Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos −/− ). Materials and methods iNos −/− mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E 2 , superoxide and leucostasis were significantly (p<0.05) increased in retinas of WT mice diabetic for 2 months compared with nondiabetic WT mice. All of these abnormalities except PARmodified proteins in retinas were inhibited (p<0.05) in diabetic iNos −/− mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with nondiabetic WT controls, these increases being significantly inhibited in diabetic iNos −/− mice (p<0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos −/− mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos −/− mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.

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Section: Resultsmentioning

confidence: 93%

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

et al. 2007

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“…The role of VEGF in causing inflammation during diabetic retinopathy has also been demonstrated by studies showing that increases in VEGF expression are correlated with increased levels of ICAM-1 immunoreactivity and leukostasis in the retinas of diabetic animals (Hammes et al, 1998;Joussen et al, 2001;Joussen et al, 2002;Miyamoto et al, 1999;Murata et al, 1996;Qaum et al, 2001). The VEGF 165 isoform is thought to be critically involved in the retinal vascular inflammatory response to diabetes in that isoform-specific blockade of VEGF 165 suppresses leukostasis and restores normal blood-retinal barrier function in diabetic rats (Ishida et al, 2003).…”

Section: Vegf and Vascular Inflammation-vegf Is A Potent Inducer Of Vmentioning

confidence: 91%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…12 Under deep anesthesia, the mouse was cardiac perfused with rhodamine-conjugated concanavalin A (Rho-Con A; Vector Laboratories, Peterborough, UK), followed by PBS. Eyes were fixed in 4% PFA for 1 hour at room temperature (RT), then retinas wholemounted in Vectashield (Vector Laboratories).…”

Section: Perfusion Assaysmentioning

confidence: 99%

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

Nagai

Leithner

Izumi-Nagai

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function.METHODS. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies.RESULTS. The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction. CONCLUSIONS.The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.Keywords: animal models, neovascularization, VEGF-A T he transformative nature of recent therapeutic developments for neovascular age-related macular degeneration (nAMD) has triggered an exponential increase in ophthalmic drug development efforts over the past decade. 1 The most prevalent assay used to benchmark potential new nAMD compounds and therapeutic strategies is rodent laser-induced choroidal neovascularization (lCNV). [2][3][4][5] This model is used to assess antiangiogenic activity and the ability to reduce vascular permeability, two hallmarks of nAMD. Moreover, because of the ease of imaging the posterior pole, lCNV is often used as a secondary pharmacology model during drug development for other conditions, such as cancer. However, the lCNV model has several limitations, including acute, intense laser injury to the photoreceptors, RPE, and choriocapillaris to induce angiogenesis, the accumulation of hypertrophic scar tissue, and a natural regression of the neovascularization. 6 Therefore, factors that initiate the CNV, and long-term analysis of the consequences of the neovessels to the retina, cannot be readily studied. Here we describe a novel genetic model of multifocal, bilateral spontaneous choroidal neovascularization (sCNV), which leads to early, persistent neovascular lesions that leak and lead to retinal edema, local gliosis and focal photoreceptor dysfunction, and death. Approximately 10% to 15% of the lesions will eventually anastomose with the...

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Leukocyte-Mediated Endothelial Cell Injury and Death in the Diabetic Retina

Cited by 512 publications

References 12 publications

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Vascular endothelial growth factor in eye disease

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

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