Physiology of Retinal Pericytes

描述（由申请人提供）：我们的长期目标是阐明 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早期症状发病后不久就丧失了生命功能 是视网膜微循环的自动调节控制。的 由此导致的血流分布的低效率损害了 功能，并最终，视网膜神经元，神经胶质细胞和血管的活力 细胞 目前，我们对糖尿病如何改变 微血管功能是有限的知识的机制， 局部血管活性信号调节视网膜中的毛细血管灌注。我们 拟议的研究是基于一个新的工作假设。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诱导的 通过间隙连接途径电紧张性地传递到近端周细胞。 这种细胞间传递是必要的，因为近端，而不是远端， 周细胞含有调节直径所必需的收缩装置 微血管腔的一部分使用双穿孔贴片记录和其他 技术，我们将比较细胞间通信内 从对照组视网膜新鲜分离的含周细胞的微血管， 糖尿病大鼠 为了解决糖尿病破坏远端到近端 视网膜微血管系统内的通信，我们的具体目标， 拟议的研究将测试以下假设：（1）在糖尿病中， 视网膜周细胞之间的电紧张性传递 血管活性信号通过其作用于远端的转导机制， 毛细血管部位促进血管近端部分的收缩或松弛， （2）PKC-β亚型在含周细胞的微血管中起关键作用， 微血管中缝隙连接通路被破坏的机制 糖尿病视网膜和（3）ET/A内皮素受体介导的破坏， 糖尿病微血管内的细胞间通讯。 从长远来看，阐明糖尿病破坏细胞内蛋白质的机制， 局部血管活性信号调节毛细血管灌注的能力将 促进新战略的发展， 预防这种疾病的威胁视力的并发症。

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.