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

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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.