Physiology of Retinal Pericytes

描述(由申请人提供)：我们的长期目标是澄清 早期破坏微血管功能的病理生理机制 糖尿病视网膜病变的病程。发病后不久就丧失了生命功能 糖尿病的主要原因是视网膜微循环的自我调节控制。这个 导致血流分配效率低下，损害了 功能，最终，视网膜神经元、神经胶质细胞和血管的生存能力 细胞。 目前，我们对糖尿病如何改变的理解存在一个关键差距 微血管功能是对其机制的有限了解 局部血管活性信号调节视网膜内的毛细血管灌流。我们的 拟议的研究是基于一种新的工作假说。也就是说，电压变化 由作用于远端毛细血管部位的血管活性信号引起的 通过缝隙连接通路以电子方式传递到近端周细胞。 这种细胞间的传递是必要的，因为近端，而不是远端， 周细胞含有调节直径所需的收缩装置。 微血管的管腔。使用双穿孔补丁记录和其他 技术，我们将比较细胞间通信在 新鲜从对照组和对照组视网膜分离的含有周细胞的微血管 糖尿病大鼠。 为了解决糖尿病破坏远端到近端的机制 在视网膜微血管系统内的沟通，我们的 拟议的研究将检验以下假设：(1)在糖尿病患者中， 视网膜周细胞之间的电渗性传递损害 血管活性信号作用于远端的转导机制 毛细血管部位引起血管近端的收缩或松弛 含有周细胞的微血管，(2)PKC-β亚型在 微血管缝隙连接通路被破坏的机制 糖尿病视网膜和(3)ET/A内皮素受体介导血管紧张素转换酶 糖尿病微血管内的细胞间通讯。 从长远来看，阐明糖尿病扰乱 局部血管活性信号调节毛细血管血流的能力将 促进制定新的战略以改善，并有望， 预防这种疾病危及视力的并发症。

DESCRIPTION (provided by applicant): Our long-range objective is to elucidate the pathophysiological mechanisms that disrupt microvascular function early in the course of diabetic retinopathy. A vital function lost soon after the onset of diabetes is the autoregulatory control of the retinal microcirculation. The resulting inefficiency in the distribution of blood flow compromises the function, and eventually, the viability of retinal neurons, glia and vascular cells. At present, a critical gap in our understanding of how diabetes alters microvascular function is the limited knowledge of the mechanisms by which local vasoactive signals regulate capillary perfusion in the retina. Our proposed studies are based on a new working hypothesis. Namely, voltage changes induced by vasoactive signals that act at distal capillary sites must be transmitted electrotonicly via gap junction pathways to proximal pericytes. This intercellular transmission is necessary because proximal, but not distal, pericytes contain the contractile apparatus necessary to regulate the diameter of the microvascular lumen. Using dual perforated-patch recordings and other techniques, we will compare intercellular communication within pericyte-containing microvessels freshly isolated from retinas of control and diabetic rats. To address the mechanisms by which diabetes disrupts distal-to-proximal communication within the retinal microvasculature, the specific aims of our proposed studies will test the hypotheses that (1) in diabetes a disruption of electrotonic transmission between retinal pericytes compromises the transduction mechanism by which a vasoactive signal acting at a distal capillary site elicits a contraction or relaxation of the proximal portion of a pericyte-containing microvessel, (2) PKC-beta isoforms play a critical role in the mechanism by which gap junction pathways are disrupted in microvessels of the diabetic retina and (3) ET/A endothelin receptors mediate disruption of intercellular communication within diabetic microvessels. Over the long-term, elucidating the mechanisms by which diabetes disrupts the ability of local vasoactive signals to regulate capillary perfusion will facilitate the development of new strategies to ameliorate, and hopefully, prevent sight-threatening complications of this disease.