The purpose of this study was to evaluate functional and funduscopic outcomes amongst patients receiving multiple treatments with macular laser photocoagulation for clinically significant diabetic macular edema. A record review was conducted of patients who had multiple macular laser treatments for diabetic macular edema. As part of routine follow-up for diabetic macular edema, visual acuity and funduscopic findings were assessed before a given laser treatment and at 6 months afterwards. The study included 64 eyes from 41 patients. There was no statistically significant difference between the proportion of eyes that showed funduscopic improvement after treatment 1 versus the proportion of eyes that improved after subsequent treatments. For the first laser treatment, 44 of the 64 eyes (69%) showed funduscopic improvement in edema. 35/64 (55%) of eyes showed improvement after the second treatment (p=0.15); 29/40 (72.5%) eyes showed improvement after the third treatment (p=0.85); 15/18 (83.3%) eyes showed improvement after treatments[greater than or equal to]4 (p=0.36). Similarly, in terms of visual acuity outcomes, there was no statistically significant difference between the proportion of eyes with preserved visual acuities after treatment 1 compared to repeat treatments. This study found that the majority of eyes that receive re-treatment after initial laser therapy will respond with an improvement in macular edema.

Introduction Retinal vascular reactivity is impaired in patients with diabetes and is thought to be involved in the onset and progression of diabetic retinopathy (DR). Previous studies that have utilized hyperoxia to assess retinal vascular reactivity have been limited due to confounding factors associated with the administration of oxygen and have used a variety of different instruments to measure retinal blood flow. The influence of blood glucose at the time of blood flow assessment has also not been systemically investigated. The specific aims of each Chapter are as follows: Chapter 3: To compare three systems used to administer hyperoxia to human subjects. Chapter 4: To quantify the magnitude and timeline of change of retinal hemodynamic parameters induced by an isocapnic hyperoxic stimulus. Chapters 5, 6 and 7: To quantify the magnitude of change of retinal hemodynamic parameters induced by hyperoxia, hyperglycemia and combined hyperoxia / hyperglycemia, respectively, in groups of diabetic patients with no clinically visible, and mild-to-moderate, DR and in age-matched subjects without diabetes. Methods Chapter 3: Subjects breathed air followed by oxygen, or oxygen plus carbon dioxide using a non-rebreathing system, or air followed by oxygen using a sequential rebreathing system. The magnitude of change and variability of CO2 concentrations was compared between systems. Chapter 4: Baseline retinal blood flow data was acquired while the subjects breathed air using a sequential rebreathing system. An isocapnic hyperoxic stimulus was initiated and maintained for 20 minutes. Air was then re-administered for 10 minutes. Retinal blood flow measurements were acquired every minute over the course of the study. The magnitude of change of each hemodynamic parameter was determined by fitting individual data with a sigmoidal function. For Chapter 5, 6 and 7 diabetic patients with no clinically visible, and mild-to-moderate, DR were stratified into groups based upon their retinopathy status. Age-matched non-diabetic subjects were recruited as controls. Baseline retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to (a) hyperoxia, (b) hyperglycemia and (c) combined hyperoxic / hyperglycemic stimuli. Change in hemodynamic parameters was compared between groups and correlated with objective measures of retinal edema. Results Chapter 3: The difference in group mean end-tidal CO2 levels between baseline and hyperoxia was significant for oxygen administration using a non-rebreathing system. The sequential rebreathing technique resulted in a significantly lower variability of individual CO2 levels than either of the other techniques. Chapter 4: An ~11% decrease of diameter, ~36% decrease of velocity and ~48% decrease of blood flow was observed in response to isocapnic hyperoxia in young, healthy subjects. A response time of 2.30??0.53 minutes and 2.62??0.54 minutes was observed for diameter and velocity, respectively. Chapter 5: Retinal blood velocity, flow, and WSR significantly decreased in response to isocapnic hyperoxia in all groups. The magnitude of the reduction of blood flow was significantly reduced with increasing severity of retinopathy. There was a significant relationship between baseline objective edema index values and retinal vascular reactivity. Chapter 6: A significant change in blood glucose level was observed for all groups. No significant change in any hemodynamic parameter was found in patients with diabetes and in age-matched subjects without diabetes. Chapter 7: Retinal blood velocity and flow significantly decreased in all groups in response to combined hyperoxic / hyperglycemic provocation. The vascular reactivity response was not significantly different across the groups. Conclusions Chapter 3: Control of CO2 is necessary to attain standardized, reproducible hyperoxic stimuli for the assessment of retinal vascular reactivity. Chapter 4: Arteriolar retinal vascular reactivity to isocapnic hyperoxic provocation occurs within a maximum of 4 minutes. Although there was a trend for diameter to respond before velocity, the response characteristics were not significantly different between diameter and velocity. Different response characteristics of the retinal vasculature to transmural pressure mediated autoregulation as opposed to metabolic mediated vascular reactivity are suggested. Chapter 5: The vascular reactivity response in terms of the reduction of blood flow relative to baseline was significant in all groups but the magnitude of the change in flow was significantly reduced with increasing severity of retinopathy. A loss of retinal vascular reactivity is indicated in patients with moderate DR without clinically evident diabetic macular edema (DME), and in patients with DME. Chapter 6: Unaltered retinal arteriolar blood flow was found 1 hour after glucose ingestion in patients with diabetes and in age-matched subjects without diabetes. These results do not support the theory that retinal blood flow is affected by an acute increase of blood glucose in diabetic patients and in subjects without diabetes. Chapter 7: The vascular reactivity response to a combined hyperoxic / hyperglycemic provocation produced a pronounced reduction in blood flow. Unlike the response to hyperoxia alone, the vascular reactivity response was not significantly different across the groups. This suggests that hyperglycemia may influence the retinal vascular reactivity response to hyperoxia.

No description available.

PURPOSE: Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy. This study aims to approach diabetic macular edema and diabetic retinopathy as ischemic conditions and explores a potential treatment through hyperoxia. The study measured changes in retinal thickness, visual acuity, and contrast sensitivity in subjects receiving normobaric oxygen. METHODS: Fifty-one patients with diabetic macular edema at Beth Israel Deaconess Medical Center Eye Clinic (Boston, MA) received oxygen via a face mask at 5 liters per minute for 3 hours. Retinal thickness at the central subfield and maximal retinal thickness were measured using optical coherence tomography. Contrast sensitivity, best corrected visual acuity, and intraocular pressure were measured before and after oxygen as well. RESULTS: Macular thickness from diabetic macular edema decreased by an average of 2.09% (p < .05) at the point of maximal thickness, and by 0.88% (p < .05) at the central subfield. Vision also improved by an average of 0.043 LogMAR units (p < .05). Changes in macular thickness and visual acuity were non-significant in healthy control eyes that received oxygen. The results of hyperoxia on contrast sensitivity were indeterminate. CONCLUSIONS: We found that normobaric hyperoxia for 3 hours reduces macular thickness from diabetic macular edema and improves visual acuity. This study offers additional evidence that diabetic macular edema is an ischemic disorder and suggests that oxygen therapy may serve as an alternate or complimentary treatment of DME. / 2020-06-17T00:00:00Z

ObjetivosEstudiar el papel de la extracción de la membrana limitante interna (MLI) durante la vitrectomía posterior por vía pars plana (VPP), en el tratamiento quirúrgico de lo agujero macular (AM) y de lo edema macular crónico diabético (EMCD). Hemos estudiado las tasas de éxito clínico de la extracción de la MLI durante la VPP. Además hemos analizado el procedimiento técnico de extracción de la MLI, el aporte de la extracción de la MLI en la resolución clínica del EMCD después de la VPP y el valor de la tomografía de coherencia óptica (TCO) en el seguimiento de pacientes con EMCD y AM.El objetivo secundario consistía en establecer una correlación clínico-patológica mediante el examen histológico de la MLI. Este estudio abarcaba los descubrimientos histológicos y las diferencias de la MLI observadas mediante microscopia electrónica de transmisión (MET) y microscopia óptica (MO).Material y MétodosEstudio prospectivo de un año de 28 pacientes, no randomizado, no comparativo, con dos grupos de pacientes: 1) grupo con AM; 2) grupo con EMCD resistente al tratamiento láser.Los pacientes habían sido sometidos, antes y después de la VPP, a un examen oftalmológico: refracción objetiva, mejor agudeza visual (AV) corregida con teste de Snellen, medición de la presión intraocular, biomicroscopia, examen del fondo ocular y oftalmoscopia indirecta. El seguimiento postoperatorio fue efectuado durante el primer año a un día, una semana, 1, 3, 6 y 12 meses del postoperatorio. Los pacientes fueron sometidos a angiografía fluoresceínica digital, fotografía del fondo de ojo y mapado macular con TCO, como exámenes diagnósticos complementarios. Todos los pacientes fueron sometidos a la VPP y el objetivo principal era la disección epiretiniana y extracción de la MLI. Las MLIs fueron preparadas para un análisis con MO y MET. ResultadosEn el grupo con AM formado por diez ojos, seis tenían AM de tipo 2 y 3 y cuatro de tipo 4 (clasificación de Gass). Cinco pacientes presentan AM idiopáticos. Todos, salvo uno, mantuvieron o mejoraron la mejor AV corregida al final del estudio. La mejora de la VA era significativa estadísticamente sólo después del tercer mes del postoperatorio. El seguimiento mediante OCT demostró que el cierre del los AM fue alcanzado en nueve de ellos. La TCO pudo acompañar la evolución anatómica del cierre del agujero. En los 18 pacientes con EMCD, trece ojos mejoraron la AV, en dos no se produjo ningún cambio y tres empeoraron la AV, al final del seguimiento. La mejora de la AV comenzó a ser significativa entre el tercer y sexto mes del postoperatorio. El espesor foveal postoperatorio se redujo de manera significativa y progresiva respecto al observada en el preoperatorio. Hemos observado una disminución graduada y evidente del espesor macular paralelamente con una mejora progresiva de la AV: cuanto menos espessa era la fovea (TCO), mayor resultaba la mejor AV corregida. Hemos analizado las características ultraestructurales de la MLI normal en las retinas extraídas de dos donadores de ojos y comparado la MLI obtenida de los ojos sometidos a la VPP. Hemos realizado el examen histopatológico en 10 muestras del grupo con AM. Hemos podido observar la presencia de la MLI en 9 muestras. Hemos encontrado residuos de retina neurosensorial asociada con la superficie retinal de la MLI en 3 muestras. Pocas MLI presentaban un componente celular asociado con la superficie vítrea. En algunas MLI, hemos observado la presencia de fragmentos condensados de la hialoides posterior, a veces asociado con componente celular. Hemos llevado a cabo 75 mediciones correspondientes a distintos segmentos de la MLI. Los resultados han demostrado una significativa diferencia (p = 0.00011) entre el promedio del espesor de la MLI en el grupo con AM y en máculas normales. Al comparar el promedio de espesor observado en el grupo con AM con los obtenidos en el grupo con EMCD (2.2 ± 0.78 µm), la diferencia era siempre significativa (p = 0.03).En las muestras diabéticas examinadas mediante MET, hemos podido observar la presencia de la MLI en 7 muestras sobre 10. En 3 muestras sobre 10 no había ninguna MLI y la membrana epiretiniana presentaba una gran cantidad de matriz extracelular (colágeno y una gran variabilidad de células). El único descubrimiento histopatológico observado en 5 muestras mediante MET consistía en segmentos de MLI sin componentes fibrilares o celulares. Cuatro muestras presentaban una abundante disposición de colágeno compatible con el espesoramiento de la membrana hialoides o MER. Distintos tipos que rodeaban el colágeno extracelular componen la población celular asociada al tejido diabético: a) células glials; b) células fibroblásticas; c) células epiteloides; d) células plasmáticas macrófagas. En la MET hemos podido demostrar la presencia de componentes retinales neurosensoriales asociadas con la superficie retiniana de la MLI en 3 muestras.ConclusionesGrupo de Agujeros Maculares: 1. La VPP asociada a la extracción de la MLI es un procedimiento de utilidad para el tratamiento quirúrgico de los AM. En el presente estudio prospectivo de un año, la tasa de cierre anatómico fue de un 90% y la mejor media de la AV final corregida se obtuvo en los ojos con éxito anatómico.2. La TCO contribuyó para el diagnóstico, se presentó como una alternativa no invasiva para la evaluación del estado foveal y permitió documentar y analizar la evolución del cierre anatómico de los AM.Grupo de Edema Macular Diabético:1. El presente estudio clínico prospectivo de un año demostró los beneficios de la extracción de la MLI, mediante VPP, como tratamiento quirúrgico del EMCD. La extracción de la MLI conllevó a una disminución del engrosamiento de la retina, a la resolución clínica del edema macular y a una mejor AV.2. La TCO permitió un seguimiento cualitativo del perfil de la retina y un análisis cuantitativo de las pequeñas variaciones del espesor macular. El espesor de la macula ha disminuido significativamente al final del primer mes del postoperatorio (p = 0,00016) comparado con una mejoría significativa de la AV corregida a partir del sexto mes de seguimiento clínico (p = 0,05).3. Mediante MO y MET, el estudio histológico mostró la ausencia de fragmentos de MLI en algunos de los especimenes analizados. Algunas piezas histológicas eran membranas epirretinianas o la hialoides posterior engrosada. Ambos Grupos:1. La correlación clínico-patológica indicó que la presencia de elementos de la retina neurosensorial observados en la cara retiniana de algunos especimenes de MLI fue extraída de ojos que presentarían una peor AV final corregida.2. El espesor de la MLI observado en el grupo de AM fue mayor que el observado en el grupo de EMCD (p = 0,03) que, a su vez, fue mayor que el espesor observado en la MLI de la retina normal (p = 0,00003).

Introduction Retinal vascular reactivity is impaired in patients with diabetes and is thought to be involved in the onset and progression of diabetic retinopathy (DR). Previous studies that have utilized hyperoxia to assess retinal vascular reactivity have been limited due to confounding factors associated with the administration of oxygen and have used a variety of different instruments to measure retinal blood flow. The influence of blood glucose at the time of blood flow assessment has also not been systemically investigated. The specific aims of each Chapter are as follows: Chapter 3: To compare three systems used to administer hyperoxia to human subjects. Chapter 4: To quantify the magnitude and timeline of change of retinal hemodynamic parameters induced by an isocapnic hyperoxic stimulus. Chapters 5, 6 and 7: To quantify the magnitude of change of retinal hemodynamic parameters induced by hyperoxia, hyperglycemia and combined hyperoxia / hyperglycemia, respectively, in groups of diabetic patients with no clinically visible, and mild-to-moderate, DR and in age-matched subjects without diabetes. Methods Chapter 3: Subjects breathed air followed by oxygen, or oxygen plus carbon dioxide using a non-rebreathing system, or air followed by oxygen using a sequential rebreathing system. The magnitude of change and variability of CO2 concentrations was compared between systems. Chapter 4: Baseline retinal blood flow data was acquired while the subjects breathed air using a sequential rebreathing system. An isocapnic hyperoxic stimulus was initiated and maintained for 20 minutes. Air was then re-administered for 10 minutes. Retinal blood flow measurements were acquired every minute over the course of the study. The magnitude of change of each hemodynamic parameter was determined by fitting individual data with a sigmoidal function. For Chapter 5, 6 and 7 diabetic patients with no clinically visible, and mild-to-moderate, DR were stratified into groups based upon their retinopathy status. Age-matched non-diabetic subjects were recruited as controls. Baseline retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to (a) hyperoxia, (b) hyperglycemia and (c) combined hyperoxic / hyperglycemic stimuli. Change in hemodynamic parameters was compared between groups and correlated with objective measures of retinal edema. Results Chapter 3: The difference in group mean end-tidal CO2 levels between baseline and hyperoxia was significant for oxygen administration using a non-rebreathing system. The sequential rebreathing technique resulted in a significantly lower variability of individual CO2 levels than either of the other techniques. Chapter 4: An ~11% decrease of diameter, ~36% decrease of velocity and ~48% decrease of blood flow was observed in response to isocapnic hyperoxia in young, healthy subjects. A response time of 2.30±0.53 minutes and 2.62±0.54 minutes was observed for diameter and velocity, respectively. Chapter 5: Retinal blood velocity, flow, and WSR significantly decreased in response to isocapnic hyperoxia in all groups. The magnitude of the reduction of blood flow was significantly reduced with increasing severity of retinopathy. There was a significant relationship between baseline objective edema index values and retinal vascular reactivity. Chapter 6: A significant change in blood glucose level was observed for all groups. No significant change in any hemodynamic parameter was found in patients with diabetes and in age-matched subjects without diabetes. Chapter 7: Retinal blood velocity and flow significantly decreased in all groups in response to combined hyperoxic / hyperglycemic provocation. The vascular reactivity response was not significantly different across the groups. Conclusions Chapter 3: Control of CO2 is necessary to attain standardized, reproducible hyperoxic stimuli for the assessment of retinal vascular reactivity. Chapter 4: Arteriolar retinal vascular reactivity to isocapnic hyperoxic provocation occurs within a maximum of 4 minutes. Although there was a trend for diameter to respond before velocity, the response characteristics were not significantly different between diameter and velocity. Different response characteristics of the retinal vasculature to transmural pressure mediated autoregulation as opposed to metabolic mediated vascular reactivity are suggested. Chapter 5: The vascular reactivity response in terms of the reduction of blood flow relative to baseline was significant in all groups but the magnitude of the change in flow was significantly reduced with increasing severity of retinopathy. A loss of retinal vascular reactivity is indicated in patients with moderate DR without clinically evident diabetic macular edema (DME), and in patients with DME. Chapter 6: Unaltered retinal arteriolar blood flow was found 1 hour after glucose ingestion in patients with diabetes and in age-matched subjects without diabetes. These results do not support the theory that retinal blood flow is affected by an acute increase of blood glucose in diabetic patients and in subjects without diabetes. Chapter 7: The vascular reactivity response to a combined hyperoxic / hyperglycemic provocation produced a pronounced reduction in blood flow. Unlike the response to hyperoxia alone, the vascular reactivity response was not significantly different across the groups. This suggests that hyperglycemia may influence the retinal vascular reactivity response to hyperoxia.

Although bevacizumab is one of the most commonly used treatments for DME and AMD, there are concerns regarding safety and effectiveness due to its off-label use. The study objectives were to determine if: 1) the risk of cardiovascular/ hemorrhagic events (safety) and visual impairment (effectiveness) differed by bevacizumab use (i.e., use vs. non-use and number of treatments) among DME and AMD patients; and 2) direct medical costs differed between DME and DME control patients. A retrospective cohort analysis was conducted with Texas Medicaid medical and prescription data (9/1/07-12/31/12) for patients: 18- 63 years, continuously enrolled 1-year pre- and post-index, and diagnosed with DME or AMD. The index date was the first date of diagnosis. The dependent variables were: 1) cardiovascular/hemorrhagic risk; 2) visual impairment; 3) direct medical costs. The independent variables were bevacizumab use and number of bevacizumab treatments. Covariates were disease state, Charlson Comorbidity Index (CCI) score, total medication use, number of laser treatments, and demographics. Propensity scoring technique was used to match: 1) bevacizumab users and non-users; and 2) DME and DME control cohorts. Descriptive analyses, logistic regression, Cox-regression, and generalized linear models were employed. A final cohort of 3,647 DME, 297 AMD, and 57,897 DME control patients were included. The majority (DME and AMD) was between 45-63 years of age (86.6%), Hispanic (54.0%), and female (65.1%). The mean total number of unique medications and mean CCI were 2.7 ± 3.4 and 6.0 ± 3.3, respectively. Total direct medical costs/person (Mean (±SD)) incurred by DME, DME control, and AMD subjects in the post-index period were $6,704(±9,338), $5,495(±10,153), and $4,935(±12,702), respectively. No differences in cardiovascular/ hemorrhagic risk were found between bevacizumab users and non-users. The claims data lacks the detail to determine the effectiveness of bevacizumab. DME control patients had lower overall direct medical costs than DME patients (p<0.0001). In conclusion, although bevacizumab is a less expensive off-label alternative of ranibizumab, the choice between bevacizumab and ranibizumab should be made through careful consideration. However, as the use of anti-VEGF agent increases, further research should be conducted to determine if any changes in cardiovascular adverse events occur. / text

PURPOSE: Diabetes Mellitus (DM) is one of the most prevalent metabolic diseases worldwide and can lead to ocular complications such as diabetic retinopathy (DR). As chronic hyperglycemia leads to endothelial pathologies in the retina, diabetic macular edema (DME) develops and worsens visual acuity. Current treatment methods include laser photocoagulation, intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections, and surgical interventions. This case report explores the effects of nocturnal normobaric hyperoxia (NNBH) treatment in a patient with DME. METHODS: A 64-year-old pseudophakic man with bilateral DME regularly treated with anti-VEGF injections was instructed to self-administer 40% fraction of inspired oxygen (FiO2) at 5 liters per minute (LPM) for 6 to 8 hours per day during sleep. Retrospective data of visual acuity (VA), optical coherence tomography (OCT) imaging, and number of injections during a one-year time frame prior to starting NNBH was compared with newly collected data of a one-year time frame while on NNBH. RESULTS: The patient was treated with a total of 12 anti-VEGF injections in the year prior to starting NNBH treatment. After one year of supplemental oxygen, subject’s VA stabilized to 20/20 in both eyes. When comparing average values of OCT data prior to NNBH and during NNBH, all measurements including central macular thickness (CMT), maximum macular thickness (MMT), foveal volume (FV), and total macular volume (TMV) decreased anywhere from 5.4% to 20.3%, reflecting a stabilization of the retina bilaterally. Subject did not require any intravitreal injections during NNBH treatment. After one month of planned cessation of NNBH, DME recurred. CONCLUSION: This model case demonstrates NNBH may be a novel treatment approach in reducing DME and improving VA in patients with DR. NNBH can be a cost-effective, convenient, and accessible therapy for patients with complications from diabetic retinopathy.

Un endothélium vasculaire rétinien quiescent est essentiel dans l’approvisionnement et le maintien de l’homéostasie tissulaire afin d’assurer la fonction visuelle. L’hyperglycémie chronique dans le diabète peut mener à des complications reliées à plusieurs changements structuraux et fonctionnels de l’endothélium. Ces changements se manifestent souvent par des vaisseaux instables et hyperperméables, résultant en un tissu rétinien inadéquatement perfusé. Ces altérations sont rencontrées dans la pathophysiologie de l’œdème maculaire diabétique (OMD) qui affecte plus du quart des diabétiques. L’inhibition du facteur de perméabilité vasculaire VEGF-A a révolutionné le traitement de l’OMD, mais est aussi associée à des effets secondaires non négligeables reliés à leur non-spécificité et à une compréhension incomplète des mécanismes régulant la perméabilité vasculaire. Un ciblage spécifique de l’endothélium permettant la récupération de la quiescence et la stabilité physiologique réduisant l’hyperperméabilité pourrait fournir un nouvel outil thérapeutique. La BMP9 (Bone morphogenetic protein 9), qui est mise en circulation par le foie, est connue comme facteur de quiescence et de stabilité vasculaire ainsi que pour son effet sur l’homéostasie du glucose. Ces aspects étant peu documentés dans un contexte diabétique, nous avons évalué les capacités de la BMP9 sur la stabilisation de l’endothélium rétinien et ses effets paracrines/autocrines sur la gluconéogenèse hépatique. Nous avons démontré que la signalisation canonique de la BMP9/Smad1,5,9 via son récepteur spécifique à l’endothélium Alk1, était déficiente dans un modèle murin de diabète, ce qui exacerbe l’hyperperméabilité endothéliale rétinienne. À l’inverse, la surexpression de la BMP9 par un modèle murin de livraison adénovirale récupère la perméabilité physiologique, associée principalement à un renforcement des jonctions interendothéliales en limitant l’action du VEGF. De plus, nous avons trouvé que la BMP9 améliore le contrôle glycémique chez les souris diabétiques par l’inhibition de la gluconéogenèse hépatique, via la voie non-canonique Alk3/FOXO1. Fondamentalement, ce travail met en évidence les mécanismes régissant la perméabilité endothéliale dans un contexte diabétique, fournissant une alternative thérapeutique contre l’OMD. La régulation de la perméabilité rétinienne par la BMP9 s’effectue à plusieurs niveaux, indirectement par le contrôle glycémique, et directement par la solidification jonctionnelle de la barrière endothéliale rétinienne, réhabilitant ainsi la quiescence et la stabilité de l'endothélium physiologique. / A quiescent retinal vascular endothelium is essential for the supply and maintenance of tissue homeostasis to ensure proper visual function. Chronic hyperglycemia in diabetes can lead to multiple complications related to several structural and functional changes in the endothelium, characterized by unstable and hyperpermeable vessels resulting in an inadequately perfused retinal tissue. These alterations are encountered in the pathophysiology of diabetic macular edema (DME), which affects more than a quarter of diabetics. Inhibition of the vascular permeability factor VEGF-A has revolutionized the treatments of DME but is associated with non-negligible side effects related to their non-specific action combined with an incomplete understanding of the mechanisms regulating vascular permeability. Specific endothelial targeting aiming to recover quiescence and reducing hyperpermeability could provide new therapeutic tools for the treatment or prevention of DME. BMP9 (Bone morphogenetic protein 9), which is produced by the liver, is known as a vascular quiescence and stability factor as well as for its effects on glucose homeostasis. Since these aspects are poorly documented in a diabetic context, we investigated BMP9’s capabilities on endothelium stabilization and its paracrine/autocrine effects on hepatic gluconeogenesis. In our studies, we found that the canonical BMP9/Smad1,5,9 signaling, via its physiological Alk1 endothelium-specific receptor, was deficient in a murine model of diabetes, which exacerbates retinal endothelial hyperpermeability. In contrast, adenoviral overexpression of BMP9 recovers physiological permeability, which was primarily associated with the enhancement of interendothelial junctions by limiting the action of VEGF. In addition, we found that BMP9 improves glycemic control in diabetic mice by inhibition of hepatic gluconeogenesis via the non-canonical ALK3/FOXO1 pathway. Fundamentally, this work highlights new insights of the mechanisms governing endothelial permeability in a diabetic context, providing a therapeutic alternative against DME. Regulation of retinal permeability by BMP9 occurs on several levels, indirectly, through glycemic control, and directly through the junctional solidification of the hyperglycemic retinal endothelial barrier, thus rehabilitating the quiescence and stability of the physiological endothelium.

L’œdème maculaire est une complication majeure de nombreuses pathologies rétiniennes induisant la cécité. Les traitements actuels ne sont pas curatifs. Ce sont des injections intraoculaires de corticostéroïdes et d'anti-VEGF. Les mécanismes d'action de ces médicaments sont mal connus dans l'œil car ces thérapies ont été initialement développées pour des pathologies non-oculaires (tels que l'asthme et les maladies auto-immunes pour les corticostéroïdes et les cancers pour certains anti-VEGF). De plus, les effets bénéfiques de ces molécules sont contrebalancés par des effets secondaires graves (glaucomes et cataractes pour les corticostéroïdes) et la résistance au traitement. Le projet vise à élucider les mécanismes d'action oculaires des corticostéroïdes et anti-VEGF; dans le but d'identifier de nouvelles cibles thérapeutiques pour le traitement de l’œdème maculaire. Ce travail a porté sur : 1) La compréhension des mécanismes des corticostéroïdes et de leurs récepteurs (le récepteur aux glucocorticoïdes ou GR et le récepteur aux minéralocorticoïdes ou MR) suite à l’injection intravitréene de corticostéroïdes ou d’aldostérone chez le rat. Nous avons ainsi : -1.1. Identifier les protéines partenaires du GR et du MR avant et après traitements par une approche protéomique (immunoprécipitations endogènes suivies d’une analyse par spectrométrie de masse). -1.2. Identification les gènes cibles dont l'expression est modulée par les corticostéroïdes ou l’aldostérone par ARN-sequencing. 2) L'identification des mécanismes d’action des aux anti-VEGFs et leur comparaison avec des molécules de même nature physico-chimique. 3) L’identification des gènes différentiellement exprimés entre la rétine périphérique et la macula (zone d’acuité visuelle susceptible à la formation d’œdèmes) chez le singe (modèle qui possède, comme l’homme, une macula). Ceci afin de comprendre pourquoi la macula est particulièrement sensible. 4) L’analyse et la comparaison de ces différents traitements. Ces études ont permis d’identifier les cofacteurs des récepteurs aux corticostéroïdes, ainsi que la dynamique de leurs interactions avant et après traitement à la corticostérone et à l’aldostérone; ainsi que les gènes dont l’expression est régulée par les corticostéroïdes et les anti-VEGF. L’analyse croisée des données, des analyses bioinformatiques ainsi que l’étude bibliographique des protéines et gènes identifiés nous ont permis d’établir une liste restreinte de cibles potentielles des traitements anti-œdémateux, dans le but final de potentialiser l’effet de ces traitements, trop souvent associés à des effets secondaires qui limitent considérablement leur(s) action(s) bénéfique(s) sur la fonction visuelle dans le traitement de l’œdème maculaire. / Macular Edema is a major complication of numerous retinal pathologies that lead the blindness. The available treatments (intra-ocular injection of corticosteroids and anti-VEGF) do not cure this disease. The ocular mechanisms of action of these drugs are not very well understood. In fact, these molecules have been initially developed for non-ocular pathologies, such as asthma, auto-immune diseases (for corticosteroid) and cancers (for anti-VEGF). In addition, the beneficial effects of these drugs are counteracted by their side effects (cataracts and glaucoma for corticosteroids) as well as resistance to treatment. The project aims at unraveling the ocular mechanisms of action of corticosteroids and anti-VEGF; in order to identify new therapeutic targets for the treatment of macular edema. The project focused on: 1) The understanding of the mechanisms of the corticosteroids and their receptors after an intravitreal injection of Corticosterone or Aldosterone in the rat model. We therefore: 1.1. Identified the partner proteins of the glucocorticoid and mineralocorticoid receptors before and after treatment, using a proteomic approach. 1.2. Identified the target genes which expression is modulated by the corticosteroid using the RNA-Sequencing technique. 2) The identification of the mechanisms of action of anti-VEGF molecules and their comparison with molecules that have similar physico-chemical structure. 3) The identification of differentially expressed genes between the retina and the macula in the monkey model. This aimed at understanding why the macula is particularly sensitive to edemas. 4) The analysis and comparison of these treatments. We were able to identify co-factors for corticosteroids receptors as well as the dynamics of these interactions (before and after treatment), as well as the genes which expression is regulated by the corticosteroids or anti-VEGF. The analysis of the bio-informatic data as well as the bibliographic study of the identified proteins and genes allowed us to establish a list of partiMacularly interesting genes that are potentially therapeutic targets for the treatment of macular edema.