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Retinal neurovascular injuries are a leading cause of vision loss in young adults presenting unmet therapeutic needs. Neurovascular injuries damage homeostatic communication between endothelial, pericyte, glial, and neuronal cells through signaling pathways that remain to be established. To understand the mechanisms that contribute to neuronal death, we use a mouse model of retinal vein occlusion (RVO). Using this model, we previously discovered that after vascular damage, there was non-apoptotic activation of endothelial caspase-9 (EC Casp9); knock-out of EC Casp9 led to a decrease in retinal edema, capillary ischemia, and neuronal death. In this study, we aimed to explore the role of EC Casp9 in vision loss and inflammation. We found that EC Casp9 is implicated in contrast sensitivity decline, induction of inflammatory cytokines, and glial reactivity. One of the noted glial changes was increased levels of astroglial cl-caspase-6, which we found to be activated cell intrinsically by astroglial caspase-9 (Astro Casp9). Lastly, we discovered that Astro Casp9 contributes to capillary ischemia and contrast sensitivity decline after RVO (P-RVO). These findings reveal specific endothelial and astroglial non-apoptotic caspase-9 roles in inflammation and neurovascular injury respectively; and concomitant relevancy to contrast sensitivity decline.
Retinal neurovascular injuries are a leading cause of vision loss in young adults presenting unmet therapeutic needs. Neurovascular injuries damage homeostatic communication between endothelial, pericyte, glial, and neuronal cells through signaling pathways that remain to be established. To understand the mechanisms that contribute to neuronal death, we use a mouse model of retinal vein occlusion (RVO). Using this model, we previously discovered that after vascular damage, there was non-apoptotic activation of endothelial caspase-9 (EC Casp9); knock-out of EC Casp9 led to a decrease in retinal edema, capillary ischemia, and neuronal death. In this study, we aimed to explore the role of EC Casp9 in vision loss and inflammation. We found that EC Casp9 is implicated in contrast sensitivity decline, induction of inflammatory cytokines, and glial reactivity. One of the noted glial changes was increased levels of astroglial cl-caspase-6, which we found to be activated cell intrinsically by astroglial caspase-9 (Astro Casp9). Lastly, we discovered that Astro Casp9 contributes to capillary ischemia and contrast sensitivity decline after RVO (P-RVO). These findings reveal specific endothelial and astroglial non-apoptotic caspase-9 roles in inflammation and neurovascular injury respectively; and concomitant relevancy to contrast sensitivity decline.
Human life expectancy has been significantly extended, which poses major challenges to our healthcare and social systems. Aging-associated cognitive impairment is attributed to endothelial dysfunction in the cardiovascular system and neurological dysfunction in the central nervous system. The central nervous system is considered an immune-privileged tissue due to the exquisite protection provided by the blood-brain barrier. The present review provides an overview of the structure and function of blood-brain barrier, extending the cell components of blood-brain barrier from endothelial cells and pericytes to astrocytes, perivascular macrophages and oligodendrocyte progenitor cells. In particular, the pathological changes in the blood-brain barrier in aging, with special focus on the underlying mechanisms and molecular changes, are presented. Furthermore, the potential preventive/therapeutic strategies against aging-associated blood-brain barrier disruption are discussed.
Background. Despite the significant achievements in understanding the mechanisms of diabetic retinopathy (DR), the active search for new approaches and testing directions for its treatment continues today. Aim: To determine the current state of understanding of the mechanisms of development and directions of treatment of diabetic retinopathy. Materials and methods. An information search for the results of scientific research was conducted in the online databases PubMed, Web of Science, Scopus, and Google Scholar using keywords. The search depth is 10 years. The search was performed by two independent authors. 178 sources were selected for analysis, of which 53 that met the search criteria were used. Results. From a pathophysiological point of view, DR is a complex of progressive changes in the microcirculatory channel, which lead to ischemia, neovascularization, increased permeability of the hematoretinal barrier, and macular edema. At the same time, the predominantly inflammatory nature of the damage with a sluggish chronic course and damage to retinal neurons and microvascular disorders was established. The universal mechanism of DR can be considered oxidative stress, which connects all biochemical and molecular pathways induced by hyperglycemia. Important mechanisms are loss of pericytes, changes in gene expression, activation of signaling cascades Ras/Raf-1/MEK/ERK, p38-MAPK, endothelial dysfunction and recruitment of leukocytes and monocytes, activation of NF-κB, HIF-1 and VEGF pathways, activation of apoptosis and pyroptosis. Existing methods of DR treating require significant expansion with the use of targeted therapy aimed at specific pathogenetic pathways. Conclusion. The discovery of new mechanisms of DR and the search for new directions of targeted therapy is an urgent task of modern ophthalmology.
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