Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension

项目总结 高血压是心脑血管疾病的首要危险因素。流行病学 研究已经证明了中年高血压的有害影响，特别是长期存在的 高血压，对晚年认知障碍的影响。精致调节脑血流(CBF)，传递 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，对于保持正常的大脑功能，如认知，至关重要。这一时刻到时刻的调整 大脑中的局部血流被称为功能性充血。我们最近的工作展示了一部小说 信号通路，毛细血管到小动脉的电信号，是功能性充血的主要因素。 这项建议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，关于毛细血管到小动脉的电信号， 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，生命- 时间高血压可显著损害功能性充血和毛细血管与小动脉之间的联系 在8个月大的雄性BPH/2J小鼠中发出信号，这一年龄接近于人类的第五个十年。 目标1中的研究将机械地检查高血压进展过程中的性别差异。 高血压BPH/2J小鼠功能性充血及毛细血管到小动脉电信号的损伤 和一株血压正常的对照品系(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了不同程度的益处 充血不足。使用三种临床上使用的降压药，它们通过不同的方式发挥作用 药理机制(即钙通道阻滞剂、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EX 雄性和雌性BPH/2J小鼠体内和体内毛细血管到小动脉的信号转导。持续不断的反- 高血压小鼠治疗开始后，往往会模拟高血压发展的情景 发生在人类身上的。此外，我们将检测血浆中的醛固酮浓度，以检验这一假设 血浆醛固酮参与了抗高血压药物的类别依赖性疗效。 总而言之，通过应用复杂方法和治疗方法的创新组合 干预，这项提议应该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和 “量身定做”的降压药方案。

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.