Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension

项目概要 高血压是心脑血管疾病的首要危险因素。流行病学 研究表明中年高血压的有害影响，尤其是长期存在的 高血压，对晚年认知障碍。精细调节脑血流量（CBF），输送 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 活动对于维持认知等正常的大脑功能至关重要。这种时时刻刻的调整 大脑中的局部血流称为功能性充血。我们最近的工作展示了一种新颖的 信号通路，毛细血管到小动脉的电信号传导，是功能性充血的主要贡献者。 该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、组织和全身水平上毛细血管到小动脉的电信号传导， 使用多基因高血压小鼠模型（BPH/2J 小鼠）。我们的初步研究表明，生活- 时间性高血压会导致功能性充血的严重损害和毛细血管到小动脉的破坏 8 个月大的雄性 BPH/2J 小鼠中的信号传导，该年龄大约相当于人类 50 岁的年龄。 目标 1 的研究将机械地检验高血压诱发的疾病进展中的性别差异。 高血压 BPH/2J 小鼠功能性充血和毛细血管-小动脉电信号传导受损 和正常血压对照小鼠品系（BPN/3J）。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不同程度的益处 充血不足。采用三种临床使用的抗高血压药物，其作用机制不同 药理机制（即 Ca2 通道阻滞剂、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，体内功能性充血和前 雄性和雌性 BPH/2J 小鼠的体内和体内毛细血管到小动脉信号传导。持续的反 对小鼠进行高血压治疗将在出现高血压后开始，以模仿经常发生的情况 发生在人类身上。此外，我们将检查血浆醛固酮浓度来检验以下假设： 血浆醛固酮有助于抗高血压药物的类别依赖性疗效。 总之，通过应用复杂方法和治疗的创新组合 干预措施，该提案应提供概念上新的转化见解，包括丰富的 有关潜在新颖治疗方法的信息，例如高血压的针对性别的治疗方法和 “量身定制”的抗高血压药物治疗方案。

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.