Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes

早期糖尿病期间内皮素-1 系统激活和视网膜微血管失调

• 批准号: 10504529
• 负责人: TRAVIS W HEIN
• 金额: $ 37.88万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504529
• 关键词: Address; Adult; Age; Animal Model; Animals; Blindness; Blood Flow Velocity; Blood Vessels; Blood flow; Clinical; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Disease; Electroretinography; Endothelin-1; Endothelin-converting enzyme 1; Endothelium; Event; Eye; Eye diseases; Family suidae; Functional disorder; Goals; Health; Human; Inflammatory; Insulin-Dependent Diabetes Mellitus; Ischemia; Knowledge; Lead; Link; MAPK8 gene; Microcirculation; Microvascular Dysfunction; Modeling; Molecular; Molecular Target; Morphology; N-terminal; Neural Retina; Neurons; Nutrient; Ocular Physiology; Outcome; Oxygen; Pathology; Pathway interactions; Perfusion; Phosphotransferases; Physiological; Production; Proteins; ROCK1 gene; Regulation; Research; Retina; Retinal Diseases; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Streptozocin; Structure; System; Testing; Time; United States; Vasoconstrictor Agents; Vasomotor; Vision; aged; arteriole; base; blood damage; constriction; diabetic; differential expression; effective therapy; experience; extracellular; improved; innovation; insight; knock-down; novel; p38 Mitogen Activated Protein Kinase; preservation; relating to nervous system; response; retinal damage; retinal ischemia; sight restoration; stress kinase; targeted treatment; treatment strategy; type I diabetic; vasoconstriction; venule

Diabetes mellitus causes microvascular complications in the retina and is a leading cause of blindness in the United States. Treatments to restore vision are limited. Reduced retinal blood flow occurs in early diabetes, suggesting that vasomotor dysregulation of retinal arterioles and/or venules leading to ischemia may contribute to later retinal damage. However, no study has examined both arteriolar and venular vasomotor function together in the retina of same diabetic subjects. Thus, a gap in knowledge is the limited understanding of mechanisms for retinal arteriolar/venular vasomotor dysregulation in early diabetes to yield treatment before overt pathology. Excessive production of vasoconstrictor and inflammatory agent endothelin-1 (ET-1) in the retina occurs in early diabetes, so in-depth insight into molecular events regulating vasomotor responses to ET-1 in health and disease has clinical implication. This proposal is based on evidence in type 1 diabetic pigs showing reduced retinal blood flow at 2-wk diabetes, along with elevated retinal lactate and diminished oscillatory potentials in the electroretinogram, indicating retinal ischemia and neural abnormality. Also, vitreous ET-1 level and retinal arteriolar endothelin- converting enzyme-1 (ECE-1) activity were elevated in diabetic pigs. Because ET-1 is derived from ECE-1 and causes vasoconstriction via Rho kinase (ROCK) signaling, activation of ECE-1/ROCK may lead to retinal vasomotor dysregulation and flow deficiency in early diabetes. Interestingly, diabetes enhances retinal venular, but not arteriolar, constriction to ET-1 by activating reverse-mode Na+-Ca2+ exchanger (NCX), possibly involving Na+-H+ exchanger-1 (NHE1) and stress kinases (p38 and JNK). Thus, the objective of this study is to unveil the sequential molecular pathways for vasomotor dysregulation of retinal arterioles and venules that promote retinal ischemia in early diabetes. The central hypothesis is that early diabetes activates microvascular ECE-1 leading to enhanced ET- 1 production, which promotes retinal arteriolar constriction via Ca2+-dependent ROCK2/JNK signaling. In early diabetes, the elevated ET-1 not only elicits retinal venular constriction via Ca2+-dependent ROCK1/JNK axis but also augments the response by further promoting Ca2+ entry through activation of the p38/NHE1/NCX axis. The cooperative promotion of arteriolar and venular constrictions to elevated ET-1 contributes to retinal ischemia and neural abnormality. Two specific aims will be pursued to support the hypothesis: (1) Determine roles of ET-1 system activation and its molecular signaling in promoting retinal arteriolar constriction and consequent retinal ischemia via Ca2+-dependent ROCK2/JNK axis in early diabetes. (2) Determine roles of ET-1 system activation and its molecular signaling to augment retinal venular constriction with consequent retinal ischemia via Ca2+- dependent ROCK1/JNK axis and activated p38/NHE1/NCX signaling pathway in early diabetes. Outcomes will advance the knowledge of diabetes-induced retinal complications and suggest effective molecular targets for improving and protecting retinal microvascular perfusion of the retina in early-stage diabetes before development of retinal structure damage.

糖尿病引起视网膜微血管并发症，是美国失明的主要原因。 States.恢复视力的治疗是有限的。视网膜血流量减少发生在早期糖尿病，这表明 视网膜小动脉和/或小静脉的血管调节异常导致缺血，可能有助于后期视网膜病变。 损害然而，还没有研究同时检查视网膜小动脉和小静脉血管功能， 同样的糖尿病患者因此，知识上的差距是对视网膜病变机制的有限理解。 早期糖尿病的小动脉/小静脉血管功能失调，以在明显病理学之前获得治疗。过度 视网膜中血管收缩剂和炎症剂内皮素-1（ET-1）的产生发生在早期糖尿病中， 因此，对健康和疾病中调节血管对ET-1反应的分子事件的深入了解， 临床意义这一建议是基于1型糖尿病猪显示视网膜血流量减少的证据 在糖尿病2周时，沿着视网膜乳酸升高和视网膜电图中振荡电位降低， 表明视网膜缺血和神经异常。此外，玻璃体ET-1水平和视网膜小动脉内皮素- 转化酶-1（ECE-1）活性升高。由于ET-1来源于ECE-1， 通过Rho激酶（ROCK）信号传导的血管收缩，ECE-1/ROCK的激活可导致视网膜血管收缩， 早期糖尿病的失调和血流缺乏。有趣的是，糖尿病会增强视网膜小静脉，而不是小动脉， 通过激活反向模式Na+-Ca 2+交换器（NCX）（可能涉及Na+-H+交换器-1）收缩ET-1 （NHE 1）和应激激酶（p38和JNK）。因此，本研究的目的是揭示序列分子 视网膜小动脉和小静脉的血管调节异常促进早期视网膜缺血的途径 糖尿病核心假设是，早期糖尿病激活微血管ECE-1，导致ET-1水平升高。 1的产生，其通过Ca 2+依赖性ROCK 2/JNK信号传导促进视网膜小动脉收缩。月初 糖尿病时，ET-1升高不仅通过Ca ~（2+）依赖的ROCK 1/JNK轴引起视网膜小静脉收缩， 还通过激活p38/NHE 1/NCX轴进一步促进Ca 2+进入而增强应答。的 协同促进小动脉和小静脉收缩以升高ET-1有助于视网膜缺血， 神经异常本研究的两个具体目标是：（1）确定ET-1的作用 系统激活及其分子信号传导在促进视网膜小动脉收缩和随后视网膜病变中的作用 糖尿病早期通过钙依赖ROCK 2/JNK轴引起缺血(2)确定ET-1系统激活的作用 以及其通过Ca 2 +-介导的增加视网膜小静脉收缩并随之发生视网膜缺血的分子信号传导。 依赖ROCK 1/JNK轴和激活p38/NHE 1/NCX信号通路在早期糖尿病中的作用。成果将 推进糖尿病引起的视网膜并发症的知识，并提出有效的分子靶点， 改善和保护发展前早期糖尿病视网膜的视网膜微血管灌注 视网膜结构损伤