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Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension

项目3：慢性高血压导致的脑血流调节受损

基本信息

批准号：
10447831
负责人：
Masayo Koide
金额：
$ 25.45万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
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/10447831
关键词：
Abbreviations Affect Age Aldosterone Amlodipine Angiotensin Receptor Animals Antihypertensive Agents Atenolol Attenuated Award Blood capillaries Blood flow Brain Calcium Channel Capillary Endothelial Cell Cardiovascular Diseases Cardiovascular system Centers of Research Excellence Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Chronic Clinical Cognition Data Dementia Development Dose Elderly Endothelial Cells Estrogens Experimental Animal Model Extramural Activities Female Funding Future Goals Hormones Human Hyperemia Hypertension Impaired cognition Life Losartan Measures Modeling Molecular Mus Neurons Nutrient Oxygen Pharmacology Plasma Play Preparation Regimen Regulation Risk Role Scientist Severities Sex Differences Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Systemic blood pressure Testing Therapeutic Therapeutic Intervention Time Tissues Translational Research United States National Institutes of Health Vascular Endothelium Vasodilation Vermont Work antagonist arteriole base beta-adrenergic receptor blood pressure reduction brain health cardiovascular health cardiovascular risk factor channel blockers clinically relevant cognitive function epidemiology study functional disability functional restoration hypertension treatment hypertensive in vivo innovation insight inward rectifier potassium channel male middle age mouse model multiphoton imaging normotensive novel novel therapeutic intervention protective effect relating to nervous system sex voltage

项目摘要

PROJECT SUMMARY Hypertension is the leading risk factor for cardiovascular and cerebrovascular diseases. Epidemiological studies have demonstrated the deleterious influence of midlife hypertension, especially long-standing hypertension, on later-life cognitive impairment. Exquisite regulation of cerebral blood flow (CBF), delivering adequate amounts of oxygen and nutrients that is spatially and temporally matched to ever-changing neuronal activity, is crucial to maintain proper brain function such as cognition. This moment-to-moment adjustment of local blood flow in the brain is known as functional hyperemia. Our recent work has demonstrated a novel signaling pathway, capillary-to-arteriole electrical signaling, is a major contributor to functional hyperemia. The overall goal of this proposal is to elucidate the impact of chronic hypertension on functional hyperemia, specifically on capillary-to-arteriole electrical signaling, at the molecular, cellular, tissue and whole body level, using a murine model of poly-genic hypertension (BPH/2J mice). Our preliminary studies demonstrate that life- time hypertension causes significant impairment of functional hyperemia and disrupted capillary-to-arteriole signaling in 8-month-old male BPH/2J mice, an age that is approximated to equal humans in their fifth decade. Studies in Aim 1 will mechanistically examine sex differences in the progression of hypertension-induced impairment of functional hyperemia and capillary-to-arteriole electrical signaling in hypertensive BPH/2J mice and a normotensive control strain (BPN/3J) of mice. In Aim 2, we will elucidate whether different classes of first-line, anti-hypertensive drugs provide a differential level of benefit with respect to restoring functional hyperemia deficiencies. Employing three clinically-used anti-hypertensive drugs, which act via distinct pharmacological mechanisms (i.e., a Ca2+ channel blocker, an angiotensin receptor antagonist, and an adrenergic β receptor blocker), we will measure systemic blood pressure, in vivo functional hyperemia and ex vivo and in vivo capillary-to-arteriole signaling in male and female BPH/2J mice. The continual anti- hypertensive treatment of mice will start after the development of hypertension to mimic the scenario often occurring in humans. Further, we will examine plasma aldosterone concentrations to test the hypothesis that plasma aldosterone contributes to the class-dependent efficacy of anti-hypertensive drugs. In summary, through application of an innovative combination of sophisticated approaches and therapeutic interventions, this proposal should provide conceptually new translational insights including a wealth of information on potential novel therapeutic approaches such as sex-specific treatments for hypertension and “tailor-made” anti-hypertensive drug regimens.

项目总结