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

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Pulsatile blood flow nourishes the organs and depends on cardiac contractility, peripheral resistances and large conductance artery stiffness. Few studies reported that pulsatile flow leads to better blood pressure regulation, kidney perfusion and a reduced inflammation. Neither the impact of pulsatile flow on cerebral blood flow (CBF) regulation, nor the molecular mechanisms involved in mechanosensing and mechanotransduction are known. We hypothesize that these physiological pathways are determinant and knowing them will help develop innovative diagnostic tools tracking CBF reactivity, that is believed to be at the basis of age-related cognitive decline when impaired. Objectives Our research program has 3 objectives and will focus on the cerebral circulation: 1) to demonstrate in isolated mouse cerebral arteries that pulse pressure regulates cerebrovascular myogenic tone and endothelium-dependent shear stress sensitivity; 2) to identify the molecular pathways involved in mechanosensing and mechanotransduction connecting pulse pressure to cerebrovascular tone; 3) to modify cerebrovascular pulse pressure both in vivo and ex vivo to study the functional outcome ex vivo and on long term CBF regulation. Scientific approach We developed a unique pulse-generator in collaboration with Dr. Frédéric Lesage from the Polytechnic School of Montreal. Our new data now online demonstrate that pulse pressure increases myogenic tone and endothelial shear stress sensitivity ex vivo while regulating nitric oxide synthase activity, a response that is impaired in proatherogenic conditions and aging: this will be studied through a grant of the HSFC (2015/2018). Directly in relation to this NSERC application, our unpublished data point to the muscarinic type 5 receptor as a mechanosensor, while mechanotransduction may be dependent on NADPH oxidase 2 and angiopoietin like-2 (angptl2) to regulate cellular reactive oxygen species. We will challenge these pathways using pharmacological tools ex vivo; using in vivo delivery of endothelial-specific associated adenovirus 2 expressing targeted shRNA; and using our angptl2-/- mice. To increase pulse pressure in the cerebrovascular circulation, we will produce a transverse aortic constriction that leads to an immediate unilateral (right side) increase in pulse pressure. Imaging will be performed by 7T-MRI and OCT to measure global CBF, and pial vessel pulsatility and flow, respectively. Novelty and expected significance of the work The technical approach is unique and designed to address our question: is the pulse pressure an integrated component of the overall regulation of CBF at rest and during metabolic demand? This will help determining the range of pulse pressure that physiologically regulates cerebrovascular reactivity and CBF, and how pulse pressure transduces its signal to the cerebral arterioles.