The Effect of Blood Flow Changes in Brain Microvasculature on Pericyte-Endothelial Cell Interaction

项目总结 中风是美国和世界范围内最常见的死亡和残疾原因之一。这个 血管系统在一生中都受到精心的调节，以适应新陈代谢需求和血液的变化 在变化很大的条件下流动。然而，许多缺血性中风患者在接受治疗后未能完全康复 急性发作。这种受损的恢复在一定程度上与大脑内的灌流回流有限有关。 微循环，即使在闭塞血管恢复通畅后也是如此--这种情况被称为“无复流” 现象。血管系统内的血液循环对周围环境施加不同类型的力。 船只。这些力量是由血管细胞感知和解释的，以指导它们在 胚胎发生和调节出生后和成年生活中的重塑。最近也有人提出 多年来，在血管细胞之间交换的机械变化的下游存在信号。 具体地说，周细胞和内皮细胞整合这些信号来动态调节血管生理， 毛细血管通透性和微血管张力在健康和疾病中的变化。尽管最近在 我们对流动介导的生物力学输入的知识，潜在的分子过程及其与 体内的血流动力仍在显现，部分原因是测量这些力量的工具和模型的局限性。 力量。为了帮助填补这一知识空白，这项拟议的研究旨在调查突然变化的影响 血脑屏障的两个组成部分--周细胞和内皮细胞--的血流及其相互作用 在成熟的脑血管中，在静态条件下，血流丧失后。我们将利用体外和体内两种方式 建立周细胞和内皮细胞如何处理的机械性相互作用的模型， 解释、组织各种机械信号。此外，我们还将查看 可能伴随这种细胞相互作用的周围细胞外基质，特别是 毛细血管壁内的内皮细胞整合素α5和周细胞来源的玻璃连素。我们的初步数据显示 随着时间的推移，在急剧向静态状态转变之后的两个阶段的反应。我们建议早些时候 以快速炎症反应为标志的阶段，涉及白细胞介素1β的表达升高，覆盖于 在随后的阶段由缺氧引起的反应，这两种反应都会导致脑血管不稳定和 脑血流重建后缺血性卒中患者出血转归的风险增加。 确定导致脑部血管不稳定的关键机制决定因素 卒中的超急性期将提供有针对性的信号，这些信号在卒中进展中可能具有临床意义 治疗。

PROJECT SUMMARY Stroke is one of the most common causes of death and disability in the United States and worldwide. The vascular system is meticulously regulated throughout life to adapt to changes in metabolic demand and blood flow under widely variable conditions. Many ischemic stroke patients however fail to fully recover following an acute attack. This impaired recovery is related in part to the limited return of perfusion within the brain microcirculation, even after restoring the patency of occluded vessels – a scenario referred to as the “no-reflow” phenomenon. Blood circulating within the vascular system exerts different types of forces on the surrounding vessels. These forces are sensed and interpreted by the vascular cells to guide their development during embryogenesis and regulate remodeling during postnatal and adult life. It has been also suggested in recent years that there are signals downstream of mechanical changes that are exchanged between vascular cells. Specifically, pericytes and endothelial cells integrate these cues to dynamically regulate blood vessel physiology, capillary permeability, and changes in microvascular tone in health and in disease. Despite recent advances in our knowledge of flow-mediated biomechanical inputs, the underlying molecular processes and their link to hemodynamic forces in vivo are still emerging, in part due to limitations in the tools and models to measure these forces. To help fill this gap in knowledge, the proposed study aims to investigate the impact of abrupt changes in blood flow on two components of the blood-brain barrier -- pericytes and endothelial cells -- and their interaction in mature brain vessels under static conditions following the loss of flow. We will utilize both ex vivo and in vivo models to establish the mechanistic interactions underlying how pericytes and endothelial cells process, interpret, and organize various mechanical signals. Additionally, we will look at corresponding changes in the surrounding extracellular matrix that might accompany this cellular interplay, specifically interactions between endothelial cell integrin α5 and pericyte-derived vitronectin within the capillary wall. Our preliminary data suggests a two-phase response over time following an acute shift towards static conditions. We propose that an early stage marked by a rapid inflammatory response, involving elevated interleukin-1beta expression, is overlaid by a hypoxia-driven response in a subsequent phase, both contributing to cerebrovascular instability and an increased risk for hemorrhagic conversion of ischemic stroke patients after re-establishing cerebral blood flow. Identifying the key mechanistic determinants responsible for blood vessel destabilization in the brain during the hyper-acute phase of stroke will provide targetable signals that could be clinically significant in advancing stroke therapies.