Defining microvascular structure and function in the aged cervical spinal cord

摘要 老年人口(≥65岁)代表着美国增长最快的年龄段。根据 根据疾病控制和预防中心的数据，居住在美国的65岁或以上人口的数量 预计到2030年，美国成年人将翻一番，达到7200万，占美国总人口的20% [1]。正常衰老导致大脑皮层微血管减少近30%，显著 毛细血管密度下降，血管对代谢需求的反应，以及血管生成能力降低。这 正常衰老时血管密度和血液供应减少的现象被认为是导致 老化的大脑对缺血性损伤的“敏感”性质。老化的脊髓也容易受到损伤； 近年来，地面坠落导致脊髓损伤(Sci)是最常见的创伤之一。 出现在急诊室的老年病人所遭受的痛苦。不幸的是，我们几乎一无所知 脊髓微血管和血流动力学如何随年龄变化。本研究旨在解决这一问题。 知识鸿沟。我们推测，脑血管内皮细胞的微血管系统发生了显著的变化。 颈椎随着年龄的增长，增加了受伤的脆弱性。我们小组最近 开发了新的方法，使用强大的活体内超快对比超声(CEUS) 成像，以显示微血管内的血流，具有无与伦比的颞叶(每帧30,000帧 其次)和空间(低至50微米)分辨率。这是与其他成像方式的重要区别， 在仅从组织表面深几百微米处检查微血管流的情况下(例如， 激光散斑和双光子成像)，超快CEUS成像使我们能够检查实质内 脊髓组织全深度内的微血管结构和血流动力学 时间到了。我们将应用这一创新的活体成像技术来研究椎管内微血管解剖和 正常衰老时的功能，以及2)TSCI后年龄相关的微血管脆弱性。另外， 脑血流量和微血管密度在男性和女性之间存在差异 无论是人类模型还是啮齿动物模型。因此，正常衰老过程中的微血管变化将在 两性都有。这项研究的结果将为理解与性别和年龄相关的改变奠定基础 脊髓的静态和动态微血管功能。

Abstract The older population (≥65 years old) represents the fastest growing age group in the United States. According to the Centers for Disease Control and Prevention, the number of people 65 years of age or older living in the United States is projected to double by 2030 to 72 million adults, representing 20% of the total U.S. population [1]. Normal aging results in a nearly 30% reduction of microvasculature in the cerebral cortex with significant drops in capillary density, vascular responses to metabolic demand, and reduced angiogenic capabilities. This phenomenon of reduced blood vessel density and blood supply in normal aging is thought to underlie the “sensitive” nature of the aging brain to ischemic injuries. The aged spinal cord is also vulnerable to injuries; in recent years, ground levels falls resulting in spinal cord injuries (SCI) are among the most common trauma suffered by older patients presenting to the emergency room. Unfortunately we know next to nothing about how spinal cord microvasculature and hemodynamic changes with age. The present study aims to address this knowledge gap. We hypothesize that there are significant alterations to the microvasculature in the cervical spine with aging, which confer increased vulnerability to injuries. Our group has recently developed novel methods, using powerful intravital ultrafast contrast enhanced ultrasound (CEUS) imaging, to visualize blood flow within the microvasculature with unparalleled temporal (30,000 frames per second) and spatial (down to 50 micron) resolution. An important departure from other imaging modalities, where microvascular flow is examined just a few hundred microns deep from the surface of the tissue (e.g., laser speckle and two photon imaging), ultrafast CEUS imaging allows us to examine intraparenchymal microvascular structure and blood flow hemodynamics within the entire depth of the spinal cord tissue in real- time. We will apply this innovative intravital imaging to study 1) intraspinal microvasculature anatomy and function during normal aging, and 2) age-related microvascular vulnerabilities after tSCI. Additionally, cerebral blood flow and microvascular density differences have been detected between males and females in both human and rodent models. Therefore, microvascular changes during normal aging will be examined in both sexes. Results from this study will be foundational to understanding sex and age-related alterations in both the static and dynamic microvascular function of the spinal cord.