Systemic vasculature remodeling in females: effects of the immune system and experience of pregnancy

心脏病是美国女性的主要杀手。心脏病在女性中是不同的 与男性相比，虽然荷尔蒙环境可能有助于特定性别的心血管生理， 对其他缓解因素的了解对整体健康至关重要。流行病学数据支持 怀孕是心血管健康风险的驱动因素。怀孕的生理压力揭示了 心血管固有的强项或不足，增强保护机制，或有可能 造成损害并导致心血管后果。此外，妊娠诱导的血管适应 产后继续(PP)。本申请中提出的工作源于审查的基本思想 怀孕完成后不久的心血管生物学将为心血管适应提供线索， 长期存在，因此会影响未来的心血管疾病风险。对这些持续性适应的研究 因此有望阐明心血管生物学中性别差异的机制。 T细胞在高血压和心血管疾病中发挥作用。尽管怀孕是一种状态 在T细胞池的显著变化中，PP的这些变化状态还没有完全阐明，也没有 是否在母体心血管参数的背景下对其进行了检查。此应用程序的PI为 母体免疫系统和血管生物学方面的专家，并已合作提供初步的 重组酶1缺陷小鼠(Rag1-/-)免疫缺陷可修饰PP的小鼠模型证据 阻力血管生理学。工作模型是怀孕产生T细胞，这种T细胞被增强 由于它们在血管周围组织中积累的能力，怀孕增加了血管细胞 与T细胞产生的信号相互作用并对其做出反应，这种获得性状态是差异的基础 在正常和免疫缺陷动物的血管中观察到PP。此R01应用程序提出了 以下是测试特定型号的目的： 目的1)探讨PP血管周围组织中T细胞聚集的分子机制。 巨噬细胞及其在PP血管重塑和功能中的作用 目的2)确定CD8 T细胞功能与PP结构改变之间的分子基础 全身脉管学 目的3)明确CD8重组PP血管对乙酰胆碱反应减弱的机制 Rag1-/-与未经处理的Rag1-/-小鼠的比较 当在现有人类数据的背景下进行检查时，所获得的信息将有助于设计 女性相关纵向研究，了解T细胞生物学与PP血管的联系机制 此外，我们还在开发独特的工具来预测女性未来的心血管疾病风险方面取得了进展。这个 拟议的研究涉及NHLBI的战略优先事项，包括关键挑战和引人注目的 与心血管疾病中的性别差异有关的问题，以及 NICHD。

Heart disease is a significant killer of women in the United States. Heart disease is different in women as compared to men, and while hormonal milieu likely contributes to sex-specific cardiovascular physiology, the understanding of other mitigating factors is critical for the overall health. Epidemiologic data supports the idea that pregnancy is a driver of cardiovascular health risk. The physiologic stress of pregnancy reveals inherent cardiovascular strengths or deficiencies, enhances protective mechanisms, or has the potential to cause damage with cardiovascular consequences. Moreover, pregnancy-induced vascular adaptations continue postpartum (PP). The work proposed in this application stems from the basic idea that examination of cardiovascular biology soon after pregnancy is completed will give clues to the cardiovascular adaptations that persist long-term and therefore affect future cardiovascular disease risk. Study of these persistent adaptations is therefore expected to delineate mechanisms of sex-specific differences in cardiovascular biology. T cells play a role in hypertension and cardiovascular disease. Although pregnancy is a state of significant changes in the T cell pool, the PP status of these changes has not been completely elucidated, nor has it been examined in the context of maternal cardiovascular parameters. The PIs of this application are experts in the maternal immune system and in vascular biology and have partnered to provide preliminary evidence in a mouse model that immune deficiency in recombinase 1 deficient mice (Rag1-/-) modifies PP resistance vasculature physiology. The working model is that pregnancy generates T cells that are enhanced in their ability accumulate in perivascular tissues, that pregnancy increases the ability of vascular cells to interact with and respond to signals generated by T cells, and that this acquired state underlies the differences observed PP in vessels from normal and immune deficient animals. This R01 application proposes the following aims to test a specific model: Aim 1) Delineate the molecular mechanisms underlying PP perivascular tissue accumulation of T cells and macrophages and determine their role in PP vascular remodeling and function Aim 2) Determine the molecular basis relating CD8 T cell function to structural changes observed in PP systemic vasculature Aim 3) Define mechanisms underlying decreased PP vascular responses to Acetylcholine in CD8-reconstituted Rag1-/- as compared to un-manipulated Rag1-/- mice When examined in the context of existing human data, the information obtained will aid in designing relevant longitudinal studies in women, understanding the mechanisms linking T cell biology to PP vascular homeostasis, and in developing unique tools to delineate future cardiovascular disease risk in women. The proposed research addresses NHLBI strategic priorities, including Critical Challenges and Compelling questions related to sex differences in cardiovascular disease and also elements of the overall mission of NICHD.