Mechanisms of Heterocellular Signaling at the Myoenothelial Junction

摘要 众所周知，老化的小动脉具有增加的收缩，并且动物具有总体的 高血压关于这种疾病的病因有几种假说， 这个过程中，NO的生物利用度是最一致的问题之一，因为小动脉 可能通过eNOS产生正常水平的NO，但扩张的能力已严重减弱。 其原因尚不清楚。最近我们证明了一种有效的NO清除剂， α珠蛋白在小动脉内皮中独特表达。再次，初步数据 本文所示的α珠蛋白的年龄依赖性增加， 随着NO穿过血管壁的运动。正因为如此，我们假设， 小动脉可能会增加α珠蛋白的表达，提供病理性的 “下沉”的NO，并降低这些小动脉扩张和增加的整体能力 整体血压。为了实现这一目标，我们提出了两个目标：目标1，我们将确定 老年小鼠α珠蛋白表达和功能的变化。目标2提出， α珠蛋白的基因缺失或修饰可改变血管反应性和血压 老年小鼠最后一个目标是使用我们产生的小鼠的稳定性来唯一地删除或过度- 在内皮中特异性表达α珠蛋白。我们令人兴奋的初步数据 表明α珠蛋白表达可能是血管内皮细胞的关键部分， 在老化的脉管系统中观察到的功能障碍。我们的实验室是独一无二的， 衰老与α珠蛋白表达和功能之间的可能关系， 作为原始R 01的一部分开发的试剂。

ABSTRACT It is well known that aged arterioles have increased constriction and the animals have an overall higher blood pressure. There have been several hypothesis that have arise as to the etiology of this process, with NO bioavailability being one of the most consistent issues in that the arterioles may make normal levels of NO via eNOS, but the ability to dilate has been severely diminished. The cause for this remains unknown. Recently we demonstrated that a potent NO scavenger, alpha globin, is uniquely expressed in endothelium of arterioles. Once more, preliminary data presented herein demonstrated an age-dependent increase in alpha globin that is consistent with movement of NO across the blood vessel wall. Because of this, we postulate that aged arterioles may develop increased alpha globin protein expression, providing a pathological “sink” for NO, and decreasing the overall ability of these arterioles to dilate and increasing overall blood pressure. To accomplish this, we propose two aims: Aim 1 we will determine changes in alpha globin protein expression and function in aged mice. Aim 2 proposes that genetic deletion or modification of alpha globin could alter vascular reactivity and blood pressure in aged mice. This last aim uses the stable of mice generated by us to uniquely delete or over- express alpha globin specifically in the endothelium. Our exciting preliminary data demonstrates that alpha globin protein expression could be a key part of the vascular dysfunction observed in an aging vasculature. Our lab is unique in being able to tease the possible relationship between aging and alpha globin expression and function with the mice and reagents developed as part of the original R01.