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

心脏周期允许器官的灌流。这种循环心脏泵血的结果是，我们动脉中的血液以脉动的方式流动。脉压是高(收缩)血压和低(舒张压)血压之间的差值。脉压，从而流量，是器官灌流的基础。然而，我们还不知道脉压是如何调节血流的。人们对大脑特别感兴趣，因为它高度灌流：确实，它消耗了大量的能量，但无法储存。重要的是，大脑血流量是自动调节的，这意味着尽管血压发生变化，大脑血流量仍保持相对稳定；例如，即使在高强度运动训练期间，血压可能增加一倍，心率可能增加两倍以上，大脑血流量仍将保持相当稳定，大脑将获得最佳灌流。脉压对脑血管的直接而具体的影响，从而对脑血流的影响，目前尚不清楚。在大脑之外，脉压的缺乏或脉压的异常升高对器官有害。我们的目标是证明正常的脉压是否以及如何是脑血流的重要组成部分。 我们的最新结果和由加拿大心脏和中风基金会资助收集的初步数据确定了一种潜在的机制，可以解释脉压是如何被血管细胞机械感知的。当血液流动时，它在动脉壁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，并通过调整动脉直径来调节血管张力。为了揭示这一途径，两位研究人员设计了一种独特的系统，该系统可以产生幅度和频率可控的脉压，适用于研究孤立的大脑小动脉的功能。此外，co-Pis设计了一种显微镜成像系统来测量麻醉小鼠的脑血流及其脉动性。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)验证这一已知的机制是否有助于脑血流调节，3)证明正常的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，脑血管调节对神经系统有影响，但大多未被认识到。因此，必须更好地了解脑血管系统和大脑完整性之间的联系机制。新的成像序列聚焦于搏动性脑动脉的特定标记物，可能有助于识别任何长期易患脑血管疾病和认知能力下降的患者。

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.