Study of the mechanisms of pulse-pressure dependent regulation of vascular tone

脉压依赖性血管张力调节机制的研究

• 批准号: RGPIN-2016-05509
• 负责人: Thorin, Eric
• 金额: $ 2.04万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615739
• 关键词: Study; mechanisms; pulse; pressure; dependent

The cardiac cycle permits the perfusion of the organs. A consequence of this cyclic cardiac pumping is that the blood in our arteries flows in a pulsatile manner. Pulse pressure is the difference between high (systolic) and low (diastolic) blood pressure. Pulse pressure, and thus flow, is at the basis of organ perfusion. Yet, we do not know how the pulse pressure regulates perfusion. The brain is of particular interest because it is highly perfused: indeed, it consumes a high amount of energy but cannot store it. Importantly, the cerebral blood flow is auto-regulated, meaning that it remains relatively constant despite changes in blood pressure; for example, cerebral blood flow will remain fairly constant and the brain will be optimally perfused even during a high intensity exercise training session during which blood pressure may double and heart rate more than triple. The direct and specific impact of pulse pressure on the cerebral vessels, and thus on brain perfusion, is not known. Outside the brain, absence of pulse pressure, or an abnormal rise in pulse pressure is deleterious to the organs. Our objective is to demonstrate whether, and how, normal pulse pressure is an essential component of cerebral blood flow. Our recent results and preliminary data collected with funding from CIHR and Heart & Stroke Foundation of Canada identified a potential mechanism that may explain how pulse pressure is mechanically sensed by the vascular cells. When the blood flows, its first target in the arterial wall is a single layer of cells called endothelial cells; these cells sense the mechanical stress of the pulse pressure and this translates in the regulation of the vascular tone by adjusting arterial diameter. To uncover this pathway, the co-PIs designed a unique system that generates a pulse pressure of controlled amplitude and frequency adapted to study the function of isolated small cerebral arteries. In addition, the co-PIs designed a microscopy imaging system to measure, in anesthetized mice, cerebral blood flow and its pulsatility. We therefore have unique tools 1) to identify the molecular mechanism by which endothelial cells sense pulse pressure, 2) to validate if this identified mechanism contributes to cerebral blood flow regulation, and 3) to demonstrate that normal pulse pressure is an essential component of cerebral blood flow regulation and brain structure maintenance. We believe that the cerebrovasculature regulation has an impact, mostly unrecognized, on the neuronal system. It is therefore mandatory to better understand the mechanisms linking the cerebrovasculature and the integrity of the brain. New imaging sequences focusing on specific markers of pulsatile cerebral arteries may help identifying any patient susceptible to develop cerebrovascular diseases and cognitive decline in the long-term.

心动周期允许器官的灌注。这种循环性心脏泵送的结果是我们动脉中的血液以脉动的方式流动。脉压是高（收缩压）和低（舒张压）血压之间的差值。脉搏压和血流是器官灌注的基础。然而，我们不知道脉搏压如何调节灌注。大脑是特别感兴趣的，因为它是高度灌注的：事实上，它消耗大量的能量，但不能储存它。重要的是，脑血流量是自动调节的，这意味着它保持相对恒定，尽管血压变化;例如，在一个实施例中，脑血流将保持相当恒定并且即使在高强度运动训练期间脑也将被最佳灌注血压可能会增加一倍，心率可能会增加三倍以上。脉压对脑血管的直接和具体影响，从而对脑灌注，是未知的。在脑外，没有脉压或脉压异常升高对器官有害。我们的目标是证明正常脉压是否以及如何成为脑血流的重要组成部分。 我们最近的研究结果和在CIHR和加拿大心脏与中风基金会的资助下收集的初步数据确定了一种潜在的机制，可以解释血管细胞如何机械地感知脉压。当血液流动时，它在动脉壁中的第一个目标是称为内皮细胞的单层细胞;这些细胞感知脉压的机械应力，并通过调节动脉直径来调节血管张力。为了揭示这一途径，co-PI设计了一个独特的系统，该系统产生了一个幅度和频率可控的脉压，用于研究孤立的小脑动脉的功能。此外，co-PI设计了一个显微镜成像系统来测量麻醉小鼠的脑血流量及其脉动。因此，我们有独特的工具1）确定内皮细胞感知脉压的分子机制，2）验证这种确定的机制是否有助于脑血流调节，3）证明正常脉压是脑血流调节和脑结构维持的重要组成部分。 我们认为，血管调节对神经系统有影响，但大多未被认识到。因此，必须更好地了解连接脑血管系统和大脑完整性的机制。新的成像序列专注于搏动性脑动脉的特定标志物，可能有助于识别任何易患脑血管疾病和长期认知能力下降的患者。