Brain Capillary Mechanosensation by Piezo1 Channels in Health and Disease

Piezo1 通道在健康和疾病中的脑毛细血管机械感觉

• 批准号: 10447833
• 负责人: Osama F Harraz
• 金额: $ 25.71万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447833
• 关键词: African American population; Attenuated; Behavior; Blood; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Brain; Cerebrovascular Circulation; Cerebrovascular system; Core-Binding Factor; Coupled; Disease; Electrophysiology (science); Endothelium; Engineering; Genes; Genetically Engineered Mouse; Health; High Prevalence; Hyperemia; Hypertension; Impairment; Laboratories; Laser-Doppler Flowmetry; Lead; Link; Measures; Mechanics; Mediating; Metabolic; Monitor; Mus; Neurons; Permeability; Pharmacology; Piezo 1 ion channel; Process; Property; Reporting; Retina; Role; Signal Transduction; Techniques; Testing; Vascular Endothelial Cell; Vermont; attenuation; base; blood pressure elevation; brain health; cardiovascular health; cerebral capillary; gain of function mutation; hemodynamics; human disease; hypertensive; in vivo; innovation; lens; mechanical force; mechanical stimulus; mouse model; multiphoton imaging; neurovascular coupling; normotensive; pressure; prevent; relating to nervous system; response; shear stress; somatosensory

Cerebral blood flow is exquisitely controlled to satisfy neuronal metabolic demands. An essential feature of this control is the on-demand increase in local blood flow triggered by neural activity; a process termed functional hyperemia (FH) that is coordinated by multiple neurovascular coupling mechanisms. Importantly, the increases in shear stress in response to enhanced blood flow constitute mechanical forces with the potential to impact vascular behavior. A growing body of evidence indicates that hypertension attenuates FH. Notably, uncontrolled elevation of blood pressure is associated with dramatic alterations in the hemodynamic forces imposed on the vasculature. However, the extent to which mechanosensitive properties of the cerebral circulation are impacted by hypertension has not been explored. Piezo1, a Ca2+/Na+-permeable, mechanosensitive channel expressed in vascular endothelial cells, is the major mechanosensor in brain capillaries. Intriguingly, a gain-of-function mutation in the PIEZO1 gene has been reported in African Americans populations, which show the highest prevalence of hypertension in the world (>40%). Based on the unique properties of Piezo1 channels and the essential role of endothelial Ca2+ signaling in FH, I will evaluate the following hypotheses: (1) brain capillary Piezo1 channel activity is altered during hypertension; and (2) this change in Piezo1 function is implicated in the deficits in FH that occur during hypertension. These hypotheses will be tested by directly measuring Piezo1 channel activity and by measuring cerebral blood flow in the context of normal and high blood pressure. We will use technical innovations introduced by our laboratory that include cutting-edge genetically engineered mouse models with increased or decreased Piezo1 activity and mice with endothelial-specific genetically encoded Ca2+ indicators. By viewing hyperemic 'responses' through a new lens as mechanical 'stimuli', the proposed studies envision normal and perturbed (i.e., hypertension) cerebral blood flow from a completely fresh perspective. This project has the potential to profoundly alter our understanding of cerebral blood flow dysregulation during hypertension and may reveal sorely needed new paths to treatment.

脑血流被精确地控制以满足神经元代谢的需要。这种控制的基本特征