Loss of the retinal glycocalyx in diabetes

糖尿病患者视网膜糖萼的丧失

• 批准号: 9975163
• 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 2023-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975163
• 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; Leukocytes; Matrix Metalloproteinases; Mechanics; Mediating; Microaneurysm; Microcirculation; Microvascular Dysfunction; Modeling; Nitric Oxide; Pathology; Permeability; Plasma; Production; Proteoglycan; Retina; Role; Sampling; Signal Transduction; Site; Surface; Testing; Thick; Thrombosis; Tissues; Tube; Vision; angiogenesis; 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.

糖尿病视网膜病变是成人失明的主要原因，被认为是糖尿病视网膜病变的微血管并发症。 该疾病具有视网膜微血管，其特征在于微动脉瘤，白细胞-内皮细胞粘附， 血管阻塞、通透性增加、毛细血管阻塞、新生血管形成等。 视网膜病理学的潜在因素是内皮表面层（糖萼）的损失。的 糖萼是包括蛋白聚糖（例如，多配体聚糖-1）和糖胺聚糖 (GAGs例如，在一个实施例中，硫酸乙酰肝素）。糖萼促进了血浆分子与它们之间的相互作用。 内皮受体，抑制血栓形成，屏蔽白细胞-内皮细胞粘附，转导 剪切力，并作为渗透性屏障。由于硫酸乙酰肝素可以被乙酰肝素酶切割， 多配体蛋白聚糖-1在其细胞外结构域上具有多个位点， 金属蛋白酶（MMPs），我们假设这些酶在糖尿病糖萼丢失中的作用。 通过对syndecan-1和硫酸乙酰肝素的联合攻击，糖萼的功能可能被破坏。 在许多模型中显示其增强白细胞-内皮细胞粘附。 这种粘附被认为促进糖尿病视网膜中毛细血管的闭塞，导致糖尿病视网膜的血管变性。 随后发展出不再灌注的“无细胞”毛细血管，形成缺血区。 最终，由此产生的缺氧促进了不受控制的血管生成，干扰了清晰的视力。当一个 当白细胞粘附在内皮表面时，它最终会被剪切力强制返回血流中 力，或者可替代地，以介导的机制穿过内皮（迁移）进入周围组织 血小板内皮细胞粘附分子-1（PECAM-1）。然而，PECAM-1的缺失阻止了白细胞 移行和粘附的白细胞可以被困在毛细血管内，引起持续的阻塞， 最终导致毛细血管死亡。我们和其他人已经注意到糖尿病视网膜病变中PECAM-1的丢失， 微循环，这种损失可能是由MMP介导的裂解，细胞因子- 介导的产量减少和/或蛋白酶体降解。以下具体目标涉及 糖尿病诱导关键内皮表面分子丢失导致白细胞减少的总体假设 粘附、毛细血管闭塞和无细胞毛细血管的最终发育：（1）研究假设 硫酸乙酰肝素从糖尿病视网膜微循环中的损失直接由乙酰肝素酶介导 和间接通过MMP促进的多配体蛋白聚糖-1切割，（2）确定负责多配体蛋白聚糖-1切割的机制。 糖尿病视网膜微循环中PECAM-1的丢失，通过检测表达的减少，增加了 蛋白酶体降解和从内皮细胞表面裂解，以及（3）研究假设 白细胞引起的毛细血管阻塞和无细胞毛细血管的发育可以通过以下方式减弱： 保护内皮表面层。

项目成果

Retinal hypoxia and angiogenesis with methamphetamine.

• DOI: 10.1016/j.exer.2021.108540
• 发表时间: 2021-05
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Lee M;Leskova W;Eshaq RS;Harris NR
• 通讯作者: Harris NR

The Endothelial Glycocalyx and Retinal Hemodynamics.

内皮糖脂和视网膜血流动力学。

• DOI: 10.3390/pathophysiology29040052
• 发表时间: 2022-12-17
• 期刊: PATHOPHYSIOLOGY
• 作者: Kaur, Gaganpreet;Leskova, Wendy;Harris, Norman R.
• 通讯作者: Harris, Norman R.

Retinal Physiology and Circulation: Effect of Diabetes.

• DOI: 10.1002/cphy.c190021
• 发表时间: 2020-07-08
• 期刊: COMPREHENSIVE PHYSIOLOGY
• 影响因子: 5.8
• 作者: Wright, William S.;Eshaq, Randa S.;Lee, Minsup;Kaur, Gaganpreet;Harris, Norman R.
• 通讯作者: Harris, Norman R.

Blood flow distribution and the endothelial surface layer in the diabetic retina.

• DOI: 10.3233/bir-180200
• 发表时间: 2019
• 期刊: BIORHEOLOGY
• 影响因子: 1.1
• 作者: Harris, Norman R.;Leskova, Wendy;Kaur, Gaganpreet;Eshaq, Randa S.;Carter, Patsy R.
• 通讯作者: Carter, Patsy R.

Diabetic retinopathy: Breaking the barrier.

• DOI: 10.1016/j.pathophys.2017.07.001
• 发表时间: 2017-12
• 期刊: Pathophysiology : the official journal of the International Society for Pathophysiology
• 作者: Eshaq RS;Aldalati AMZ;Alexander JS;Harris NR
• 通讯作者: Harris NR