Retinal Vasculopathy Research Articles

Human disease phenotypes associated with mutations in TREX1.

Considering that it is a single exon gene encoding a 314 amino acid protein, the genotype-phenotype landscape of TREX1 is remarkably complex. Here we briefly describe the human diseases so-far associated with mutations in TREX1, which include Aicardi-Goutières syndrome, familial chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leukodystrophy.

Molecular disorganization of axons adjacent to human lacunar infarcts

Cerebral microvascular disease predominantly affects brain white matter and deep grey matter, resulting in ischaemic damage that ranges from lacunar infarcts to white matter hyperintensities seen on magnetic resonance imaging. These lesions are common and result in both clinical stroke syndromes and accumulate over time, resulting in cognitive deficits and dementia. Magnetic resonance imaging studies suggest that these lesions progress over time, accumulate adjacent to prior lesions and have a penumbral region susceptible to further injury. The pathological correlates of this adjacent injury in surviving myelinated axons have not been previously defined. In this study, we sought to determine the molecular organization of axons in tissue adjacent to lacunar infarcts and in the regions surrounding microinfarcts, by determining critical elements in axonal function: the morphology and length of node of Ranvier segments and adjacent paranodal segments. We examined post-mortem brain tissue from six patients with lacunar infarcts and tissue from two patients with autosomal dominant retinal vasculopathy and cerebral leukoencephalopathy (previously known as hereditary endotheliopathy with retinopathy, nephropathy and stroke) who accumulate progressive white matter ischaemic lesions in the form of lacunar and microinfarcts. In axons adjacent to lacunar infarcts yet extending up to 150% of the infarct diameter away, both nodal and paranodal length increase by ∼20% and 80%, respectively, reflecting a loss of normal cell-cell adhesion and signalling between axons and oligodendrocytes. Using premorbid magnetic resonance images, brain regions from patients with retinal vasculopathy and cerebral leukoencephalopathy that harboured periventricular white matter hyperintensities were selected and the molecular organization of axons was determined within these regions. As in regions adjacent to lacunar infarcts, nodal and paranodal length in white matter of these patients is increased. Myelin basic protein and neurofilament immunolabelling demonstrates that axons in these adjacent regions have preserved axonal cytoskeleton organization and are generally myelinated. This indicates that the loss of normal axonal microdomain architecture results from disrupted axoglial signalling in white matter adjacent to lacunar and microinfarcts. The loss of the normal molecular organization of nodes and paranodes is associated with axonal degeneration and may lead to impaired conduction velocity across surviving axons after stroke. These findings demonstrate that the degree of white matter injury associated with cerebral microvascular disease extends well beyond what can be identified using imaging techniques and that an improved understanding of the neurobiology in these regions can drive new therapeutic strategies for this disease entity.

Genetic aspects of migraine

Migraine is a common disease characterized by severe headache with nausea, vomiting and hypersensitivity to sounds, light, smell. Neurological symptoms during aura period develop in 25% of patients. Genes responsible for migraine development have been identified. The mutations in familial hemiplegic migraine are better investigated. The serotonin system plays a key role in the migraine pathogenesis. It was described the syndrome of migraine-like headache occurring due impaired serotonin metabolism in patients with celiac disease. Celiac disease is a chronic polysyndrome disease, enteropathy. Arteriopathies associated with migraine are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (syndrome CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary systemic angiopathy (HSA), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).

Chapter 20 - Incontinentia pigmenti (Bloch–Sulzberger syndrome)

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome; OMIM #308300) is an X-linked dominant neurocutaneous disorder with presumed male lethality. It is usually diagnosed in female newborns based on skin features (erythematous, vesicular, or bullous eruption in linear streaks). The skin lesions evolve into a verrucous stage, followed by atrophy and scarring, leaving linear areas of hypopigmentation and hyperpigmented macules in bizarre patterns following Blaschko's lines. Systemic and neurologic complications include focal seizures and hemorrhagic cerebral infarction in infants, and retinal vasculopathy leading to blindness. Hypodontia, conical or pegged teeth, and linear areas of alopecia persist into adulthood. IP is caused by mutation of the IKBKG/NEMO gene on Xq28. Deletion of exons 4 to 10 (NEMOΔ4-10) accounts for about 80% of cases (familial and sporadic). NEMO mutation leads to loss of function of NF-κB, a critical protein that modulates cellular proliferation, apoptosis, and response to proinflammatory factors, leading to the characteristic features of IP. In female carriers, selective loss of cells expressing the mutant X-chromosome results in completely skewed X-inactivation in the majority of cases. Study of mouse models in which various components of the NF-κB pathway (including NEMO) have been knocked out has contributed significantly to our understanding of disease pathogenesis.

The Vitreoretinal Interface in Retinal Vein Occlusions – A Clue for Surgery?

Retinal vein occlusions are still one of the leading retinal vasculopathies with a strong impact on the quality of life. Despite the success in symptomatic treatment with anti-vascular endothelial growth factor (VEGF) medication, no real causal therapy has been developed so far. As most of the pathogenetic changes have been observed in the vitreoretinal interface, actual therapeutic strategies are being focused on this area. Modern surgical techniques may help to release vitreovascular traction, stop cytokine activation and improve retinal oxygenation.

Genetics of cerebral small vessel disease.

Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single-gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage.

Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare late-onset autosomal dominant systemic microvascular disease due to C-terminal truncation mutations in the three prime repair exonuclease 1 gene, TREX1 .1 Patients present with varying degrees of progressive bilateral vision loss, renal impairment, and neurologic symptoms. Cerebral MRI shows either confluent tumorlike signal alterations or multiple small white matter lesions.2,3 Herein we demonstrate a case of RVCL caused by a novel TREX1 mutation with distinct lesions on cerebral MRI and type I interferon (IFN) activation.

Assessment of perfused foveal microvascular density and identification of nonperfused capillaries in healthy and vasculopathic eyes.

To analyze the foveal microvasculature of young healthy eyes and older vasculopathic eyes, imaged using in vivo adaptive optics scanning light ophthalmoscope fluorescein angiography (AOSLO FA). AOSLO FA imaging of the superficial retinal microvasculature within an 800-μm radius from the foveal center was performed using simultaneous confocal infrared (IR) reflectance (790 nm) and fluorescence (488 nm) channels. Corresponding IR structural and FA perfusion maps were compared with each other to identify nonperfused capillaries adjacent to the foveal avascular zone. Microvascular densities were calculated from skeletonized FA perfusion maps. Sixteen healthy adults (26 eyes; mean age 25 years, range, 21-29) and six patients with a retinal vasculopathy (six eyes; mean age 55 years, range, 44-70) were imaged. At least one nonperfused capillary was observed in five of the 16 healthy nonfellow eyes and in four of the six vasculopathic eyes. Compared with healthy eyes, capillary nonperfusion in the vasculopathic eyes was more extensive. Microvascular density of the 16 healthy nonfellow eyes was 42.0 ± 4.2 mm(-1) (range, 33-50 mm(-1)). All six vasculopathic eyes had decreased microvascular densities. AOSLO FA provides an in vivo method for estimating foveal microvascular density and reveals occult nonperfused retinal capillaries. Nonperfused capillaries in healthy young adults may represent a normal variation and/or an early sign of pathology. Although limited, the normative data presented here is a step toward developing clinically useful microvascular parameters for ocular and/or systemic diseases.

Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-β/δ.

Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability. Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 were assayed by Western blot analysis. Expression of VEGFR1 and R2 was measured by quantitative RT-PCR. Last, retinal vascular permeability was assayed in vivo by Evans blue extravasation. Human retinal microvascular endothelial cell monolayers treated with VEGF for 24 hours showed decreased TEER values that were completely reversed by the highest concentration of GSK0660 (10 μM) and PPARβ/δ-directed siRNA (20 μM). In HRMEC treated with VEGF, GSK0660 stabilized tight-junctions as evidenced by Claudin-1 staining, reduced phosphorylation of Erk1/2, and reduced VEGFR1/2 expression. Peroxisome proliferator-activated receptor β/δ siRNA had a similar effect on VEGFR expression and Claudin-1, supporting the specificity of GSK0660 in our experiments. Last, GSK0660 significantly inhibited VEGF-induced retinal vascular permeability and reduced retinal VEGFR1and R2 levels in C57BL/6 mice. These data suggest a protective effect for PPARβ/δ antagonism against VEGF-induced vascular permeability, possibly through reduced VEGFR expression. Therefore, antagonism/reverse agonism of PPARβ/δ siRNA may represent a novel therapeutic methodology against retinal hyperpermeability and is worthy of future investigation.

Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms.

Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms. This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized.

Neuroretinal degeneration in relation to vasculopathy in diabetes.

Diabetic vasculopathy is still, despite all efforts to treat its late complications, the leading cause of blindness among the working-age adults in the Western world, and in the developing countries, a similar situation is created due to the catching up in welfare and in its wake an identical unhealthy diabetes-promoting lifestyle (1). The definition of diabetic retinopathy is based on observation of vascular changes. The first recognizable vascular abnormalities are microaneurysms and small hemorrhages, followed by more severe signs of vascular leakage, such as hard exudates and larger hemorrhages; vascular dropout, such as cotton wool spots; more widespread hemorrhages; and neovascularizations. The severity of the vascular changes has been graded to guide ophthalmologists in monitoring patients and treating patients in a timely fashion to prevent loss of vision (2). It has been long known that the neuroretina is affected at an early stage by diabetes-induced metabolic changes. This diabetic neuroretinal degeneration has been demonstrated in histological studies and through the measurement of functional loss with a number of functional tests (3), such as contrast vision, color vision, visual field, and dark adaptation. An important test demonstrating neuroretinal degeneration is the multifocal electroretinogram (mfERG) (4,5). Recently, with spectral domain optical coherence tomography, structural changes could be shown with decreased thickness of the ganglion cell layer and retinal nerve fiber layer (6). Signs of neuroretinal degeneration, measured with all these methods, were present in eyes even before any visible vascular pathology could be detected. This highlights the interesting concept of neuroretinal degeneration playing a role in the development of diabetic retinal vasculopathy (7–9). If neuroretinal degeneration does play a role in the subsequent development of diabetic vasculopathy, one would expect neuroretinal degeneration to precede vasculopathy. …

Neurological manifestations of dengue viral infection.

Dengue is the most common mosquito-borne viral infection worldwide. There is increased evidence for dengue virus neurotropism, and neurological manifestations could make part of the clinical picture of dengue virus infection in at least 0.5%–7.4% of symptomatic cases. Neurological complications have been classified into dengue virus encephalopathy, dengue virus encephalitis, immune-mediated syndromes (acute disseminated encephalomyelitis, myelitis, Guillain–Barré syndrome, neuritis brachialis, acute cerebellitis, and others), neuromuscular complications (hypokalemic paralysis, transient benign muscle dysfunction and myositis), and dengue-associated stroke. Common neuro-ophthalmic complications are maculopathy and retinal vasculopathy. Pathogenic mechanisms include systemic complications and metabolic disturbances resulting in encephalopathy, direct effect of the virus provoking encephalitis, and postinfectious immune mechanisms causing immune-mediated syndromes. Dengue viruses should be considered as a cause of neurological disorders in endemic regions. Standardized case definitions for specific neurological complications are still needed.

Retinal changes in visceral leishmaniasis by retinal photography.

BackgroundIn visceral leishmaniasis (VL), retinal changes have previously been noted but not described in detail and their clinical and pathological significance are unknown. A prospective observational study was undertaken in Mymensingh, Bangladesh aiming to describe in detail visible changes in the retina in unselected patients with VL.MethodsPatients underwent assessment of visual function, indirect and direct ophthalmoscopy and portable retinal photography. The photographs were assessed by masked observers including assessment for vessel tortuosity using a semi-automated system.Results30 patients with VL were enrolled, of whom 6 (20%) had abnormalities. These included 5 with focal retinal whitening, 2 with cotton wool spots, 2 with haemorrhages, as well as increased vessel tortuosity. Visual function was preserved.ConclusionsThese changes suggest a previously unrecognized retinal vasculopathy. An inflammatory aetiology is plausible such as a subclinical retinal vasculitis, possibly with altered local microvascular autoregulation, and warrants further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-527) contains supplementary material, which is available to authorized users.

Heidelberg Spectralis Ultra-Widefield Fundus Fluorescein Angiography in Infants

To describe the intraoperative use of the Heidelberg Spectralis for ultra-widefield fundus fluorescein angiography in infants. Retrospective observational case series. A modified Heidelberg Spectralis was used to perform ultra-widefield fundus fluorescein angiography in infants undergoing an examination under general anesthesia for a range of retinal vasculopathies. Peripheral angiographic findings, angiographic image acquisition time, and any complications were reviewed. A total of 22 eyes of 11 infants underwent intraoperative ultra-widefield fundus fluorescein angiography using the modified Heidelberg Spectralis. Ultra-widefield fundus fluorescein angiography was successfully performed in all infants and permitted capture of the posterior pole as well as the peripheral retina in a single shot centered on the macula. Peripheral retinal pathologies captured include neovascularization, capillary nonperfusion, and skip areas from previous laser treatment. Capturing of angiographic images took a mean time of 7.09 minutes. Image artifact from condensation of the ultra-widefield lens was noted during imaging of 1 infant. The modified Heidelberg Spectralis is an effective and reliable imaging tool for performing ultra-widefield fundus fluorescein angiography in infants. It is capable of capturing wide-angle images of high quality. The technique has advantages as an alternative to RetCam fluorescein angiography in infants undergoing an examination under general anesthesia.

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

G.P.10: The DUX4 promoter mouse: The next generation

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a 1 in 7500 incidence. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, although no consistent pattern of penetrance or severity exists. A hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. The current model of pathogenesis in FSHD involves mis-expression of the myotoxic DUX4 gene, but developing animal models has proven difficult. At previous meetings, we first described our transgenic reporter mice containing a putative DUX4 promoter cloned upstream of GFP. We generated three separate lines of DUX4 promoter-GFP mice to identify DUX4 expression patterns and the involvement of selected muscles in FSHD. In short, we found the DUX4 promoter directed GFP expression in the face and limbs of newborn and adult mice, as well as multiple cell types in the retina. Essentially all other organs were GFP negative with a few exceptions including the pancreas and brain. Closer analysis of GFP positive tissues has revealed extensive expression in both myogenic and neuronal cell types. Strikingly, all lines also showed variable penetrance and asymmetrical expression in all GFP-positive tissues, even within individual litters. We have recently created another transgenic line expressing a GFP-CRE fusion protein from the same DUX4 promoter. Importantly we see similar expression patterns to the original mice and are now using them to create an inducible DUX4 transgenic mouse. We have also created analogous AAV vectors to induce localized DUX4 expression at physiologically relevant levels. These models will aid in deciphering molecular mechanisms and developing therapeutic interventions for FSHD.

Retinal vasculopathy is reduced by dietary salt restriction: involvement of Glia, ENaCα, and the renin-angiotensin-aldosterone system.

Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin-aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin-angiotensin-aldosterone system in ischemic retinopathy. Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-α. Macroglial Müller cells maintain the integrity of the blood-retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor-sensitive epithelial sodium channel alpha (ENaCα), which is expressed in Müller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Müller cells, high salt increased ENaCα, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCα, angiotensin type 1 receptor, and mineralocorticoid receptor expression. An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin-angiotensin-aldosterone system.

Retinal drug toxicity in the absence of visible fundus changes

AbstractA variety of systemic medications cause retinal drug toxicity associated with characteristic ophthalmoscopic changes e.g. pigmentary retinopathies, crystalline retinopathies, retinal vasculopathies, or retinopathies associated with macula edema. However, altered retinal function can occur in the absence of visible fundus changes. For example, the cardiac glycosides, digoxin and digitoxin, are frequently associated with disturbances of colour vision mediated through the inhibition of sodium‐potassium ATPase. Similarly, phosphodiesterase inhibitors such as sildenafil can also act on the photoreceptor transduction cascade to cause reversible changes in colour perception, blurred vision and increased glare sensitivity. Exposure to antiepileptic drugs that modulate GABA, can also lead to altered visual function. The most significant adverse reaction occurs with vigabatrin which can cause irreversible concentric visual field loss in susceptible individuals. It is important for eye care professionals to be aware of the potential for adverse reactions associated with systemic drugs and consider the use of functional vision tests for their detection and monitoring.

Retinal vasculopathies

AbstractDrug‐induced retinal vasculopathies constitute a group of rare disorders, most often produced by quinine, aminoglycosides, hormone preparations, and interferon. IFN‐ associated retinopathy includes cotton wool spots, retinal hemorrhages and retinal micro aneurysms. Aminoglycosides were often used subconjunctivally after different ocular surgeries as a postoperative prevention of endophthalmitis and intravitreally as a method of endophthalmitis treatment. Both clinical and animal studies have shown vascular changes, including whitening of the retina, retinal hemorrhages, multiple areas of vascular leakage and macular infarction. Although the true pathogenesis remains unknown, the clinical presentation of capillary nonperfusion has suggested a primarily vascular mechanism. The mechanism of quinine‐induced retinal toxicity, although still not well understood, includes probably ischemic/ occlusive type of events occurring in the posterior retinal circulation with relative sparing of choroidal circulation. Hormone‐related retinopathy, mainly due to oral contraceptives, include among others retinal hemorrhage or emboli, macular edema, and papillary edema.

Functional links between gelatinase B/matrix metalloproteinase-9 and prominin-1/CD133 in diabetic retinal vasculopathy and neuropathy.

Retinopathy, a common cause of blindness, is a hallmark of diabetes and depends on two pathological mechanisms: vasculopathy and neuropathy. Whereas vasculopathy is well understood and has been associated with changes in gelatinase B/matrix metalloproteinase-9 (MMP-9) and other vasculotropic factors, specific markers for diabetes-induced retinal neuropathy are not yet described. Neuropathy may result from damages to the blood-retinal barrier (BRB) and from loss of neuroprotective factors. We studied diabetes-induced changes in vascular, inflammatory and regenerative markers and demonstrated that MMP-9 was increased, whereas prominin-1/CD133 was decreased in retinal extracts. Invitro, MMP-9 specifically destroyed prominin-1/CD133. Streptozotocin-induced diabetes resulted in BRB breakdown as a sign of vasculopathy and in prominin-1/CD133 destruction in photoreceptors as an in situ parameter of diabetic neuropathy. Both invivo phenotypes were completely reversed in single MMP-9 gene knockout mice, demonstrating that MMP-9 mediates both diabetes-induced retinal vasculopathy and neuropathy, with prominin-1/CD133 being a critical and specific substrate of MMP-9. This functional link between gelatinase B/MMP-9 and prominin-1/CD133 explains mechanistically both the vasculopathy and neuropathy of diabetic retinopathy and suggests that specific MMP-9 inhibition is an interesting therapeutic avenue to investigate.