Loss of the retinal glycocalyx in diabetes

糖尿病患者视网膜糖萼的丧失

• 批准号: 9321055
• 负责人: NORMAN R HARRIS
• 金额: $ 36.25万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321055
• 关键词: Address; Adhesions; Adult; Attenuated; Back; Binding; Blindness; Blood Circulation; Blood Vessels; Blood capillaries; CD31 Antigens; Cell Adhesion; Cell surface; Cessation of life; Cleaved cell; Clinical; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Docking; Dropout; Emigrations; Endothelial Cells; Endothelium; Enzymes; Experimental Models; Extracellular Domain; Glycocalyx; Glycoproteins; Glycosaminoglycans; Glypican; Health; Hemorrhage; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hypoxia; Individual; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Matrix Metalloproteinases; Mechanics; Mediating; Microaneurysm; Microcirculation; Microvascular Dysfunction; Modeling; Nitric Oxide; Pathology; Permeability; Plasma; Production; Proteoglycan; Retina; Retinal; Role; Sampling; Signal Transduction; Site; Surface; Testing; Thick; Thrombosis; Tissues; Tube; Vision; angiogenesis; capillary; cotton wool spots; cytokine; diabetic; heparanase; neovascularization; prevent; receptor; retina blood vessel structure; shear stress; syndecan

Diabetic retinopathy, the leading cause of blindness in adults, is recognized as a microvascular complication of the disease, with retinal microvessels characterized by microaneurysms, leukocyte-endothelial cell adhesion, hemorrhages, increased permeability, capillary occlusion, neovascularization, etc. We propose that an underlying contributor to the retinal pathology is the loss of the endothelial surface layer (glycocalyx). The glycocalyx is a dense layer of molecules including proteoglycans (e.g., syndecan-1) and glycosaminoglycans (GAGs, e.g., heparan sulfate). The glycocalyx facilitates the interactions between plasma molecules and their endothelial receptors, inhibits thrombosis, shields against leukocyte-endothelial cell adhesion, transduces shear force, and acts as a permeability barrier. Inasmuch as heparan sulfate can be cleaved by heparanase, and syndecan-1 has multiple sites on its extracellular domain susceptible to cleavage by matrix metalloproteinases (MMPs), we hypothesize a role for these enzymes in the loss of the glycocalyx in diabetes. With a combined attack on both syndecan-1 and heparan sulfate, the functions of the glycocalyx could be substantially lost, which has been shown in many models to enhance leukocyte-endothelial cell adhesion. Such adhesion is thought to promote the occlusion of capillaries in the diabetic retina, leading to the subsequent development of “acellular” capillaries that are no longer perfused, creating ischemic zones. Ultimately, the resulting hypoxia promotes uncontrolled angiogenesis that interferes with clear vision. When a leukocyte adheres to the endothelial surface, it can eventually be coerced back into the bloodstream by shear forces, or alternatively, cross the endothelium (emigrate) into the surrounding tissue in a mechanism mediated by platelet endothelial cell adhesion molecule-1 (PECAM-1). However, loss of PECAM-1 prevents leukocyte emigration, and adherent leukocytes can be trapped within capillaries causing continued occlusion and eventual capillary death. We and others have noted a loss of PECAM-1 from the diabetic retinal microcirculation, with this loss possibly caused by mechanisms such as MMP-mediated cleavage, cytokine- mediated decrease in production, and/or proteasomal degradation. The following specific aims address the overall hypothesis that diabetes induces the loss of key endothelial surface molecules that results in leukocyte adhesion, capillary occlusion, and eventual development of acellular capillaries: (1) Investigate the hypothesis that the loss of heparan sulfate from the diabetic retinal microcirculation is mediated directly by heparanase and indirectly by MMP-facilitated cleavage of syndecan-1, (2) Determine the mechanism(s) responsible for the loss of PECAM-1 from the diabetic retinal microcirculation, by testing for decreased expression, increased proteasomal degradation, and cleavage from the endothelial cell surface, and (3) Investigate the hypothesis that capillary occlusion by leukocytes and the development of acellular capillaries can be attenuated by protection of the endothelial surface layer.

糖尿病性视网膜病是成人失明的主要原因，被认为是微血管并发症 该疾病，带有微型神经瘤，白细胞 - 内皮细胞粘附的视网膜微血管， 出血，渗透率提高，毛细血管阻塞，新血管形成等。我们建议 视网膜病理学的基本贡献是内皮表面层（糖囊肿）的丧失。 糖脂是一层密集的分子层，包括蛋白聚糖（例如Syndecan-1）和糖胺聚糖 （例如，硫酸乙酰肝素）。糖脂促进血浆分子及其之间的相互作用 内皮受体，抑制血栓形成，屏蔽白细胞 - 内皮细胞粘合剂，转导 剪切力，充当渗透性屏障。因为硫酸乙酰肝素可以被肝素酶裂解， syndecan-1在其细胞外域上有多个位点，易受矩阵的裂解 金属蛋白酶（MMP），我们假设这些酶在糖尿病中糖脂的丧失中的作用。 通过对syndecan-1和硫酸乙酰肝素的综合攻击，糖卵形的功能可能是 在许多模型中已显示出大幅损失，以增强白细胞 - 内皮细胞粘合剂。 人们认为这种广告可以促进糖尿病性视网膜中毛细血管的阻塞，从而导致 随后不再灌注的“细胞”毛细血管的发展，形成缺血区。 最终，产生的缺氧促进了不受控制的血管生成，会干扰清晰的视力。当a 白细胞粘附到内皮表面，有时可以通过剪切将其胁迫回到血液中 或替代地介导的机制，将内皮（移民）穿过内皮（移民）到周围的组织 由血小板内皮细胞粘附分子1（PECAM-1）。但是，PECAM-1的损失阻止白细胞 移民和粘附的白细胞可能被困在毛细血管中，导致持续阻塞和 最终毛细管死亡。我们和其他人注意到糖尿病性视网膜中PECAM-1的损失 微循环，这种损失可能是由MMP介导的裂解，细胞因子 - 介导的生产减少和/或蛋白酶体降解。以下具体目的解决了 糖尿病诱导关键内皮表面分子丧失的总体假设，导致白细胞 粘附的粘附，毛细血管阻塞和事件的发展：（1）研究假设 肝素酶直接介导了从糖尿病性视网膜微循环中硫酸乙酰肝素的损失 并间接通过syndecan-1的MMP相关裂解，（2）确定负责的机制 糖尿病性视网膜微循环中PECAM-1的损失，通过测试表达降低，增加 蛋白酶体降解和从内皮细胞表面裂解，（3）研究假设 白细胞的毛细血管阻塞和细胞毛细血管的发展可能会被减弱 保护内皮表面层。