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; 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.

糖尿病会导致视网膜中的微血管并发症，是联合失明的主要原因 国家。恢复视力的治疗方法有限。糖尿病早期的视网膜血流减少，表明 视网膜动脉和/或导致缺血的静脉的血管舒缩失调可能有助于后来的视网膜 损害。然而，尚无研究检查小动脉和静脉血管舒缩功能 相同的糖尿病患者。因此，知识的差距是对视网膜机制的有限理解 早期糖尿病中的动脉/静脉血管舒张症失调，在明显病理学之前接受治疗。过多的 在糖尿病的早期，视网膜中产生血管收缩剂和炎症剂内皮素-1（ET-1）， 因此，对调节血管舒适反应ET-1的健康和疾病中的分子事件的深入了解已有 临床意义。该建议基于1型糖尿病猪的证据，显示视网膜血流减少 在2周的糖尿病中，以及视网膜乳酸升高，电图图中的振荡电位降低 表明视网膜缺血和神经异常。此外，玻璃体ET-1水平和视网膜动脉内皮素 - 在糖尿病猪中，转化酶-1（ECE-1）活性升高。因为ET-1源自ECE-1并引起原因 通过Rho激酶（岩石）信号传导的血管收缩，ECE-1/ROCK的激活可能导致视网膜血管舒缩剂 早期糖尿病的失调和流量缺乏。有趣的是，糖尿病增强了视网膜静脉，但不能增强小动脉， 通过激活反向模式Na+ -ca2+交换器（NCX）来收缩ET-1，可能涉及Na+ -H+ Cherfanger-1 （NHE1）和压力激酶（p38和JNK）。因此，这项研究的目的是揭示顺序分子 视网膜动脉和静脉的血管舒缩失调的途径，这些途径早期促进视网膜缺血的途径 糖尿病。中心假设是早期糖尿病会激活微血管ECE-1，从而增强ET- 1生产，通过Ca2+依赖性Rock2/JNK信号传导促进视网膜小动脉收缩。在早期 糖尿病，升高的ET-1不仅通过Ca2+依赖性岩石1/JNK轴引起视网膜静脉收缩 还通过激活p38/nhe1/ncx轴进一步促进CA2+进入，从而增强了响应。这 对ET-1升高的小动脉和静脉收缩的合作促进有助于视网膜缺血和 神经异常。将追求两个具体目标以支持以下假设：（1）确定ET-1的作用 系统激活及其在促进视网膜小动脉收缩和随之而来的视网膜中的分子信号传导 早期糖尿病中的Ca2+依赖性Rock2/JNK轴的缺血。 （2）确定ET-1系统激活的作用 它的分子信号传导以增强视网膜静脉收缩，随之而来的视网膜缺血通过Ca2+ - 依赖的岩石1/JNK轴和激活的p38/NHE1/NCX信号通路。结果会 促进了解糖尿病引起的视网膜并发症的知识，并提出有效的分子靶标 在发育前的早期糖尿病中改善和保护视网膜的视网膜微血管灌注 视网膜结构损伤。