Venular Control of Retinal Blood Flow

描述（由申请人提供）：了解糖尿病的微血管变化对改善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缺氧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（链脲佐菌素注射）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微血管功能障碍的局部机制，其中来自炎症细胞的介质从小静脉扩散到紧密结合的小动脉，直接或通过血管扩张剂一氧化氮的衰减诱导血管收缩。在一个相关的模型（糖尿病大鼠肠系膜微血管功能障碍）中，我们之前已经证明了与毛细血管后小静脉密切相关的小动脉中一氧化氮的大量衰减。我们假设糖尿病视网膜也是如此，一氧化氮的衰减与活性氧（如超氧化物）的增加有关。此外，我们假设局部来源于炎症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（小鼠和大鼠的视网膜），表明血栓烷合成酶的抑制逆转了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受体结合，直接诱导血管收缩。此外，血管收缩剂已被发现有助于氧化应激，抑制血栓素可急剧提高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，VEGF生成增加，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，而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素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能改善糖尿病视网膜并发症的终点。

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.