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

项目总结 据估计，全球每年约有1000万人死于高血压，但 不幸的是，95%的病例病因不明。此外，男性患高血压的风险更大。 而不是绝经前的女性。然而，绝经后，女性患高血压的风险超过了年龄- 匹配的男性，指出雌激素是预防高血压的激素。与之相对的是 雌激素的心血管保护作用，血管紧张素II(Ang II)是公认的驱动因素 高血压的症状。血管紧张素转换酶II在大脑内起作用，增加交感神经系统流出，随后 会导致血压升高。事实上，高血压患者表现出血管紧张素II和血管紧张素Ⅱ水平升高。 令人同情的过度活动。作为一种多肽激素，血管紧张素Ⅱ的体积太大，无法跨越血脑屏障而影响 缺乏血脑屏障的特殊侧脑室周围核的心血管调节，特别是 穹隆下器(SFO)。血管紧张素Ⅱ诱导的细胞应激源，包括氧化应激和内质网 在血管紧张素转换酶II诱导的高血压中，SFO内的功能障碍被强烈地牵连。然而，一体化的 SFO的这些变化导致神经元慢性变化的下游细胞机制 功能仍不清楚。有趣的是，这些应激源已经被证明可以诱导细胞衰老--a 复杂的细胞表型，其特征是细胞代谢、大分子损伤和 一种称为衰老相关分泌表型(SASP)的分泌性促炎环境。 我们在小鼠模型中的关键初步数据显示，中枢神经系统衰老有助于 高血压。更多令人兴奋的证据表明，血管紧张素转换酶II促进衰老和SASP激活。 雄性的SFO，而雌性则不是。在此基础上，目前的提案将检验雌激素是否 对SFO细胞衰老/SASP和随后的高血压发展具有保护作用。致信地址 在这一假设下，我们将全面描述男性和女性SFO细胞衰老/SASP的特征 利用分子、组织学和体内创新研究血管紧张素转换酶II诱导的高血压小鼠 成像技术。我们将进一步确定细胞衰老对SFO的功能后果 神经元和高血压的性二型性如何由SFO和II介导的相互作用驱动 衰老和雌激素。这项提案的发现有可能推动我们对 高血压病理中的性别二态脑机制，这可能刺激新的治疗方法 对男女高血压患者都适用。

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.