Venular Control of Retinal Blood Flow

视网膜血流的静脉控制

• 批准号: 7314514
• 负责人: NORMAN R HARRIS
• 金额: $ 29.3万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314514
• 关键词: Angiogenic Factor; Animal Model; Area; Binding; Biological Availability; Blood Vessels; Blood flow; Cell Death; Cells; Constriction procedure; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diffuse; End Point; Functional disorder; Hyperglycemia; Hypoxia; Inflammatory; Injection of therapeutic agent; Lead; Localized; Mediating; Mediator of activation protein; Mesentery; Modeling; Mus; Nitric Oxide; Oxidative Stress; Pattern; Play; Production; Rattus; Reactive Oxygen Species; Retina; Retinal; Retinal Diseases; Role; Smooth Muscle; Smooth Muscle Myocytes; Streptozocin; Streptozocin Diabetes; Superoxides; Thinking; Thromboxanes; Tissues; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasoconstrictor Agents; Vasodilator Agents; Week; arteriole; attenuation; countercurrent chromatography; diabetic; diabetic rat; improved; postcapillary venule; receptor; research study; vasoconstriction; venule

DESCRIPTION (provided by applicant): Understanding the microvascular changes of diabetes is crucial to the development of improved therapy. In the diabetic retina, areas of ischemic tissue are thought to lead to deficient oxygenation and the production of vascular endothelial growth factor, which enhances vascular permeability and plays a major role in retinopathy. Our preliminary data in an animal model of diabetes (streptozotocin injection) demonstrate early arteriolar constriction in the initial weeks of hyperglycemia. Experiments from our lab suggest a localized mechanism of microvascular dysfunction, in which mediators derived from inflammatory cells diffuse from venules to closely paired arterioles to induce vasoconstriction, either directly or through an attenuation of the vasodilator nitric oxide. In a related model (microvascular dysfunction in the mesentery of diabetic rats), we previously have demonstrated a substantial attenuation of nitric oxide in arterioles closely paired with postcapillary venules. We hypothesize that the same could be true in the diabetic retina, and that the attenuation in nitric oxide is related to the increase in reactive oxygen species such as superoxide. Moreover, we hypothesize that thromboxane derived locally from inflammatory cells contributes significantly to the arteriolar vasoconstriction. We have obtained exciting preliminary data (in the retina of both mice and rats) indicating that inhibition of thromboxane synthase reverses the arteriolar vasoconstriction induced by diabetes. Thromboxane is a highly potent vasoactive molecule, and can induce vasoconstriction directly by binding to its receptor on vascular smooth muscle cells. In addition, the vasoconstrictor has been found to contribute to oxidative stress, and inhibition of thromboxane acutely elevates nitric oxide bioavailability. Models of streptozotocin-induced diabetes demonstrate retinal hypoxia, increased cell death, an increase in VEGF production, and an increase in vascular permeability. We propose that vasoconstriction contributes to these deleterious consequences, and that improvements in these endpoints can be accomplished via inhibition of thromboxane and reactive oxygen species. Our specific aims are to investigate the role for thromboxane and reactive oxygen species in the early retinal arteriolar constriction induced by diabetes, and to determine whether inhibition of vasoconstriction improves endpoints of diabetic retinal complications.

描述(由申请人提供)：了解糖尿病的微血管变化对于改进治疗的发展至关重要。在糖尿病视网膜中，缺血组织区域被认为导致氧合不足和血管内皮生长因子的产生，血管内皮生长因子增强血管通透性，在视网膜病变中起主要作用。我们在糖尿病动物模型(注射链脲佐菌素)中的初步数据显示，在高血糖的最初几周，早期的小动脉收缩。我们实验室的实验表明了微血管功能障碍的一种局部机制，即来自炎性细胞的介质从小静脉扩散到紧密配对的小动脉，直接或通过减弱血管扩张剂一氧化氮来诱导血管收缩。在一个相关的模型(糖尿病大鼠肠系膜微血管功能障碍)中，我们先前已经证明，在与毛细血管后小静脉紧密配对的小动脉中，一氧化氮显著减少。我们假设在糖尿病视网膜中也可能是这样，一氧化氮的减弱与超氧化物等活性氧物种的增加有关。此外，我们假设局部来源于炎性细胞的血栓素对小动脉血管收缩有重要作用。我们已经获得了令人兴奋的初步数据(在小鼠和大鼠的视网膜中)，表明抑制血栓素合成酶可以逆转糖尿病引起的小动脉血管收缩。血栓素是一种高效的血管活性分子，可通过与血管平滑肌细胞上的血栓素A受体结合直接诱导血管收缩。此外，血管收缩已被发现有助于氧化应激，而抑制血栓素显著提高了一氧化氮的生物利用度。链脲佐菌素诱导的糖尿病模型显示视网膜缺氧，细胞死亡增加，血管内皮生长因子产生增加，血管通透性增加。我们认为，血管收缩导致了这些有害的后果，这些终点的改善可以通过抑制血栓素和活性氧来实现。我们的具体目的是研究血栓烷和活性氧在糖尿病引起的早期视网膜小动脉收缩中的作用，并确定抑制血管收缩是否改善了糖尿病视网膜并发症的终点。