Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension

项目摘要 高血压是心脑血管疾病的主要危险因素。流行病学 研究表明中年高血压的有害影响，特别是长期高血压， 高血压，对晚年认知障碍。精细调节脑血流量（CBF）， 充足的氧气和营养物质，在空间和时间上与不断变化的神经元相匹配， 活动，是至关重要的，以维持适当的大脑功能，如认知。这种时刻的调整 脑中的局部血流被称为功能性充血。我们最近的工作证明了一种新颖的 信号传导途径，即毛细血管-小动脉电信号传导，是功能性充血的主要原因。 本提案的总体目标是阐明慢性高血压对功能性充血的影响， 特别是在分子、细胞、组织和全身水平上， 使用多基因高血压的鼠模型（BPH/2 J小鼠）。我们的初步研究表明生命- 时间高血压引起功能性充血的显著损害和毛细血管-小动脉的破坏 在8个月大的雄性BPH/2 J小鼠中，该年龄近似等于人类的第50个十年。 目的1中的研究将从机制上检验高血压诱导的高血压进展中的性别差异。 高血压BPH/2 J小鼠功能性充血和毛细血管-微动脉电信号损害 和血压正常的对照品系（BPN/3 J）小鼠。在目标2中，我们将阐明不同类别的 一线抗高血压药物在恢复功能方面提供了不同水平的获益， 充血不足。采用三种临床使用的抗高血压药物，其通过不同的作用机制发挥作用。 药理学机制（即，Ca 2+通道阻断剂、血管紧张素受体拮抗剂和 肾上腺素能β受体阻滞剂），我们将测量全身血压，体内功能性充血和体外循环。 雄性和雌性BPH/2 J小鼠体内和体内毛细血管-小动脉信号传导。持续的反- 高血压治疗的小鼠将开始后，高血压的发展，以模仿的情况下，往往 发生在人类身上。此外，我们将检测血浆醛固酮浓度，以检验以下假设： 血浆醛固酮有助于抗高血压药物的类别依赖性功效。 总之，通过应用先进方法和治疗方法的创新组合， 干预，这一建议应提供概念上的新的翻译见解，包括丰富的 关于潜在的新治疗方法的信息，如高血压的性别特异性治疗， “量身定做”的抗高血压药物方案。

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.