The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension.

脑细胞衰老在高血压性别二态性中的作用。

• 批准号: 10656211
• 负责人: Samantha Annie Dow
• 金额: $ 4.07万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656211
• 关键词: Address; Adult; Affect; Age; Aging; Angiotensin II; Blood - brain barrier anatomy; Brain; Brain region; Cardiovascular system; Cell Aging; Cell Nucleus; Cells; Cellular Metabolic Process; Central Nervous System; Cessation of life; Chronic; Complex; Data; Development; Electrophysiology (science); Endoplasmic Reticulum; Estrogen Receptor alpha; Estrogens; Etiology; Excision; Female; Functional disorder; Histologic; Histological Techniques; Hormones; Hypertension; Imaging Techniques; Inflammatory; Lead; Measures; Mediating; Menopause; Molecular; Mus; Myocardial Infarction; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phenotype; Physiological; Postmenopause; Premenopause; Protective Agents; Regulation; Risk; Risk Factors; Rodent Model; Role; Signal Transduction; Stress; Stroke; Subfornical Organ; Sympathetic Nervous System; Techniques; Testing; Transgenic Organisms; Viral; Woman; Work; attenuation; blood pressure elevation; blood-brain barrier crossing; chemokine; combinatorial; cytokine; endoplasmic reticulum stress; hypertension treatment; hypertensive; in vivo; in vivo bioluminescence imaging; in vivo imaging; indexing; inflammatory milieu; innovation; male; men; mouse model; novel; novel therapeutics; peptide hormone; prevent; protective effect; senescence; sex; sexual dimorphism; stressor; therapeutic target

PROJECT SUMMARY It is estimated that about 10 million deaths worldwide each year are associated with hypertension, but unfortunately, the etiology is unknown in 95% of cases. Furthermore, the risk of hypertension is greater in men than pre-menopausal women. However, post-menopause, the female risk of hypertension exceeds that of age- matched males, pointing to the hormone estrogen as protective against hypertension. In contrast to the cardiovascular protective effects of estrogen, the hormone angiotensin II (Ang II) is well-recognized as a driver of hypertension. Ang II acts within the brain to elevate sympathetic nervous system outflow, which subsequently leads to increases in blood pressure. Indeed, hypertensive patients display elevated levels of Ang II and sympathetic overactivity. As a peptide hormone, Ang II is too large to cross the blood-brain-barrier and influences cardiovascular regulation at specialized circumventricular nuclei that lack a blood-brain-barrier, particularly the subfornical organ (SFO). Ang II-induced cellular stressors including oxidative stress and endoplasmic reticulum dysfunction within the SFO are strongly implicated in Ang II-induced hypertension. However, the integrative downstream cellular mechanisms by which these alterations in the SFO lead to chronic changes in neuronal function remains unclear. Interestingly, these stressors have been shown to induce cellular senescence - a complex cellular phenotype characterized by marked changes in cell metabolism, macromolecular damage, and a secretory pro-inflammatory environment known as the senescence associated secretory phenotype (SASP). Our key preliminary data in murine models reveals that central nervous system senescence contributes to hypertension. Additional exciting evidence indicates that Ang II drives senescence and SASP activation in the SFO of males, but not in females. Building upon this, the current proposal will test the hypothesis that estrogen is protective against SFO cellular senescence/SASP and subsequently hypertension development. To address this hypothesis, we will comprehensively characterize SFO cellular senescence/SASP in male versus female mice during Ang II-induced hypertension development using molecular, histological, and innovative in vivo imaging techniques. We will further determine the functional consequence of cellular senescence on SFO neurons and how the sexual dimorphism of hypertension is driven by the interplay between SFO Ang II-mediated senescence and estrogen. Findings from this proposal have the potential to advance our understanding of sexually dimorphic brain mechanisms in hypertension pathology, which may spur novel therapeutic treatments for hypertension in both sexes.

项目摘要 据估计，全世界约有1000万人死亡与高血压有关，但 不幸的是，在95％的病例中，病因尚不清楚。此外，男性高血压的风险更大 比绝经前妇女。但是，少年后，女性高血压风险超过年龄的风险 匹配的雄性，指出激素雌激素是防止高血压的保护作用。与 雌激素的心血管保护作用，激素血管紧张素II（ANG II）被广泛认可为驱动 高血压。 ANG II在大脑中起作用以提升交感神经系统流出，随后 导致血压升高。确实，高血压患者的ANG II和ANG II水平升高 交感的过度活动。作为肽激素，ANG II太大而无法穿越血脑屏障并影响 缺乏血脑屏障的专业核心核的心血管调节，尤其是 副骨器器官（SFO）。 ANG II诱导的细胞应激源，包括氧化应激和内质网 SFO内的功能障碍与ANG II诱导的高血压有很大的影响。但是，是综合性 SFO中这些改变导致神经元的慢性变化的下游细胞机制 功能尚不清楚。有趣的是，这些应激源已显示出诱导细胞衰老 - A 复杂的细胞表型，其特征是细胞代谢，大分子损伤和 一种被称为衰老相关的分泌表型（SASP）的分泌促炎环境。 我们在鼠模型中的关键初步数据表明，中枢神经系统衰老有助于 高血压。其他令人兴奋的证据表明，ANG II驱动衰老和SASP激活 男性的SFO，但不在女性中。在此基础上，当前的提案将检验雌激素的假设 可以保护SFO细胞衰老/SASP以及随后的高血压发育。解决 这个假设，我们将全面地表征男性与女性的SFO细胞衰老/SASP 在ANG II期间使用分子，组织学和创新的体内的小鼠诱导的高血压发育 成像技术。我们将进一步确定细胞衰老对SFO的功能后果 神经元以及高血压的性二态性如何由SFO ANG II介导的相互作用驱动 衰老和雌激素。该提案的发现有可能提高我们对 高血压病理学中的性二态脑机制，这可能刺激新型治疗治疗 两性中的高血压。