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