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

女性全身脉管系统重塑：免疫系统和怀孕经历的影响

• 批准号: 9900062
• 负责人: ELIZABETH A. BONNEY
• 金额: $ 39万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900062
• 关键词: Acetylcholine; Address; Adipose tissue; Adoptive Transfer; Affect; Animals; Antigens; Arterial Fatty Streak; B-Lymphocytes; Biology; Blood Vessels; CCR5 gene; CD31 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Communication; Cell physiology; Cells; Cellular biology; Collagen; Data; Disease; Elements; Experimental Models; Fatty acid glycerol esters; Female; Functional disorder; Future; Generations; Gestational Diabetes; Granzyme; Health; Heart Diseases; Homeostasis; Hormonal; Human; Hypertension; Immune; Immune response; Immune system; Immunological Models; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-15; Interleukin-17; Interleukin-7; Kidney Diseases; Lead; Leukocytes; Life; Link; Longitudinal Studies; Macrophage Activation; Matrix Metalloproteinases; Mediating; Mesentery; Mission; Modeling; Molecular; Mothers; Multiparity; Mus; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Pathway interactions; Phenotype; Physiological; Physiology; Play; Population; Postpartum Period; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Outcome; Premature Birth; Process; Proteins; Publishing; Rag1 Mouse; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Resolution; Risk; Role; Sex Differences; Signal Transduction; Stress; Structure; System; T-Cell Depletion; T-Lymphocyte; TNF gene; Testing; Time; Tissues; United States; Vascular System; Vascular remodeling; Vasodilator Agents; Woman; Women' s Health; Work; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; combat; cytokine; design; disorder risk; embryo/fetus antigen; epidemiologic data; experience; human data; immune activation; macrophage; men; mouse model; novel; receptor; recombinase; reconstitution; response; sex; stem; tool; trafficking; vascular factor; vascular injury; vascular smooth muscle cell proliferation; vascular stress

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.

心脏病是美国女性的一个重要杀手。心脏病在女性中是不同的 与男性相比，虽然激素环境可能有助于性别特异性心血管生理学， 了解其他缓解因素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 固有的心血管优势或缺陷，增强保护机制，或有可能 造成心血管损害。此外，妊娠诱导的血管适应性 产后继续（PP）。在本申请中提出的工作源于基本思想，即检查 怀孕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。对这些持续适应的研究 因此，预计将描绘心血管生物学中性别特异性差异的机制。 T细胞在高血压和心血管疾病中发挥作用。虽然怀孕是一种 T细胞池的显著变化，这些变化的PP状态尚未完全阐明， 是否在母体心血管参数的背景下进行了检查。此应用程序的PI为 专家在母体免疫系统和血管生物学，并已合作提供初步的 小鼠模型中的证据表明，重组酶1缺陷小鼠（Rag 1-/-）的免疫缺陷会改变PP 阻力脉管生理学。工作模型是，怀孕产生的T细胞， 在它们在血管周围组织中积累能力中，妊娠增加了血管细胞的能力， 与T细胞产生的信号相互作用并对其作出反应，这种获得的状态是差异的基础。 在正常和免疫缺陷动物的血管中观察到PP。本R 01申请建议 以下是测试特定模型的目的： 目的1）阐明PP血管周围组织T细胞聚集的分子机制， 巨噬细胞，并确定其在PP血管重塑和功能中的作用 目的2）确定PP中观察到的结构变化与CD 8 T细胞功能相关的分子基础。 全身脉管系统 目的3）确定CD 8重建的大鼠PP血管对乙酰胆碱反应降低的机制。 Rag 1-/-与未操作的Rag 1-/-小鼠相比 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 在女性中进行相关纵向研究，了解T细胞生物学与PP血管 稳态，并开发独特的工具来描述未来女性心血管疾病的风险。的 拟议的研究涉及NHLBI战略优先事项，包括关键挑战和紧迫性 与心血管疾病的性别差异有关的问题以及 NICHD。