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善治疗的发展至关重要。在糖尿病性视网膜中，缺血组织的区域被认为会导致缺氧和血管内皮生长因子的产生，从而增强了血管通透性并在视网膜病变中起主要作用。我们在糖尿病动物模型（链蛋白酶注射）中的初步数据表明，在高血糖的最初几周中，我们的早期小动脉收缩。我们实验室的实验提出了一种微血管功能障碍的局部机制，其中源自炎性细胞的介质从静脉扩散到静脉弥漫到紧密配对的小动脉，直接或通过血管舒张剂氧化物的衰减诱导血管收缩。在相关模型（糖尿病大鼠肠系膜中的微血管功能障碍）中，我们以前已经证明了与后毛细血管静脉息息的小动脉中一氧化氮的大幅衰减。我们假设在糖尿病性视网膜中可能是正确的，一氧化氮的衰减与反应性氧气（如超氧化物）的增加有关。此外，我们假设从炎症细胞本地衍生的血栓烷对小动脉血管收缩产生了重大贡献。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），表明抑制血栓烷合酶会逆转糖尿病诱导的小动脉血管收缩。血栓烷是一种高度有效的血管活性分子，可以通过在血管平滑肌细胞上与其受体结合直接诱导血管收缩。此外，已经发现血管收缩剂有助于氧化应激，并且抑制血栓烷急性升高一氧化氮的生物利用度。链蛋白酶诱导的糖尿病的模型表现出视网膜缺氧，细胞死亡增加，VEGF产生增加以及血管渗透性的增加。我们建议血管收缩会导致这些有害后果，并且可以通过抑制血栓烷和活性氧来实现这些终点的改善。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，并确定血管收缩的抑制是否可以改善糖尿病性视网膜并发症的终点。