Emerging evidence identifies increased blood pressure variability (IBPV) as a strong predictor of the vascular component of cognitive impairment and dementia, but how IBPV causes cognitive decline is not known. Components of the neurovascular unit, including endothelial cells and astrocytes express the recently discovered mechanosensitive Ca2+-permeable cation channel, Piezo1 implicated in inflammation and Alzheimer?s disease. Our group showed mechanotransduction to be enhanced in hypertension with augmented astrocyte Ca2+ and myogenic vasoconstriction. This project tests the central hypothesis that IBPV causes amplified Piezo1-mediated endothelial cell and astrocyte Ca2+ responses, which impairs cerebrovascular function and induces cognitive decline. Studies will be conducted in a novel murine model of chronic IBPV, induced by pulsatile angiotensin II infusion coupled with continuous blood pressure measurement in conscious mice. Aims 1-3 will test the hypothesis: 1) that elevated mechanostimulation at the neurovascular unit, via increased Piezo1 activation, results in hypoperfusion and cognitive decline; 2) that increased endothelial cell and astrocyte Ca2+, via increased Piezo1 activation, diminishes sensory-evoked increases in cerebral blood flow and 3) that Piezo1-induced astrocyte Ca2+ overload shifts the astrocytic population towards the proinflammatory A1 phenotype. Using both in vivo and in situ approaches, we will link macroscopic cardiovascular variables to microscopic cellular events at the NVU and assess how IBPV progressively impairs vascular, glial and neuronal function. The relationship between IBPV and cognitive decline, along with Ca2+ dynamics, will be assessed using a longitudinal approach. Mice expressing the Ca2+ indicator GCaMP6 in astrocytes and endothelial cells will be used to track the association between IBPV and aberrant Ca2+ events. A pharmacological and genetic approach will be used to test the mechanism of Piezo1 cellular pathways underlying pressure-driven vascular dysfunction and glia-driven inflammation (gliosis). Findings will establish the Piezo1 ion channel as the molecular player underlying IBPV- evoked NVU dysfunction and demonstrate its potential as a therapeutic target. We propose that augmented blood pressure variability accelerates gliosis, thereby enhancing NVU dysfunction, which, in turn, contributes to vascular cognitive impairment and dementia.
- National Institute of Neurological Disorders and Stroke
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