Role of Retinal Capillary Stiffness in Diabetic Retinopathy

项目摘要 糖尿病视网膜病变（DR）是糖尿病的一种主要的、潜在的致盲性微血管并发症 也是工作年龄人口视力丧失的主要原因。虽然目前的临床治疗 旨在解决DR的高级阶段，人们认识到更有效的DR管理 可以通过在早期阶段处理疾病来实现。糖尿病引起的视网膜炎症是 视网膜内皮细胞活化（ICAM-1表达）在DR的发病机制中起着重要作用。 在炎症中起主要作用，因为抑制ICAM-1单独阻断视网膜毛细血管白细胞停滞， 高渗透性和与DR相关的变性。但视网膜内皮细胞 (ECs)在糖尿病中被激活还没有被正确理解。由于糖尿病一直是 与经历慢性炎症的主动脉和动脉僵硬度增加有关， 询问糖尿病是否也会导致视网膜毛细血管硬化，如果是， 毛细血管僵硬促进糖尿病视网膜炎症。我们的初步数据显示，视网膜 糖尿病小鼠的毛细血管比正常小鼠的毛细血管明显更硬，这与糖尿病相关。 赖氨酰氧化酶（LOX）表达增加。LOX依赖性毛细血管的药理学抑制 硬化单独阻断与糖尿病相关的视网膜内皮ICAM-1。我们的初步研究表明 还揭示了糖尿病视网膜炎症的这种僵硬依赖性控制是由 机械敏感性和促炎性小GTdR Rho及其下游效应物ROCK， 在糖尿病小鼠和HG处理的视网膜EC培养物的视网膜毛细血管中显著上调。基于 根据这些观察，我们推测糖尿病导致LOX依赖性视网膜毛细血管硬化 Rho/ROCK升高，进而促进NF-κ B介导的内皮细胞ICAM-1表达， 视网膜炎症与早期DR相关。本提案的目的是揭示 糖尿病、视网膜毛细血管僵硬、内皮机械转导和视网膜炎症之间的关系。 为了实现这一目标，我们将努力实现以下具体目标。目标1：全面审查 LOX对视网膜毛细血管硬化依赖性炎症的药理学和遗传学抑制， 早期DR的血管病变;目的2：确定糖尿病诱导的生化 视网膜中的变化有助于LOX依赖性视网膜毛细血管硬化;以及 毛细血管硬化依赖性视网膜炎症的机械转导机制 糖尿病

PROJECT ABSTRACT Diabetic retinopathy (DR) is a major, potentially blinding, microvascular complication of diabetes and the leading cause of vision loss in the working-age population. Although current clinical therapies aim to resolve the advanced stages of DR, there is a recognition that more effective DR management can be achieved by tackling the disease at the early stage. Diabetes-induced retinal inflammation is strongly implicated in the pathogenesis of DR. Retinal endothelial activation (ICAM-1 expression) plays a major role in inflammation because inhibiting ICAM-1 alone blocks retinal capillary leukostasis, hyperpermeability, and degeneration associated with DR. But precisely how retinal endothelial cells (ECs) become activated in diabetes is not properly understood. Since diabetes has been strongly associated with increased stiffness of the aorta and arteries, which undergo chronic inflammation, we asked whether diabetes also leads to stiffening of retinal capillaries and, if so, whether the increased capillary stiffness promotes retinal inflammation in diabetes. Our preliminary data has revealed that retinal capillaries in diabetic mice are significantly stiffer than those in normal mice, which correlates with increased lysyl oxidase (LOX) expression. Pharmacological inhibition of LOX-dependent capillary stiffening alone blocks retinal endothelial ICAM-1 associated with diabetes. Our preliminary studies have also revealed that this stiffness-dependent control of retinal inflammation in diabetes is mediated by the mechanosensitive and proinflammatory small GTPase Rho and its downstream effector ROCK, which is markedly upregulated in retinal capillaries of diabetic mice and HG-treated retinal EC cultures. Based on these observations, we hypothesize that diabetes leads to LOX-dependent stiffening of retinal capillaries and elevated Rho/ROCK that, in turn, promotes NF-kB-mediated endothelial ICAM-1 expression and retinal inflammation associated with early DR. The objective of this proposal is to uncover the link between diabetes, retinal capillary stiffness, endothelial mechanotransduction, and retinal inflammation. To achieve this goal, we will pursue the following specific aims. Aim 1: To fully examine the effects of pharmacologic and genetic inhibition of LOX on retinal capillary stiffening-dependent inflammation and vascular lesions of early DR; Aim 2: To determine the extent to which diabetes-induced biochemical changes in the retina contribute to LOX-dependent retinal capillary stiffening; and Aim 3: To delineate the mechanotransduction mechanism underlying capillary stiffening-dependent retinal inflammation in diabetes.