Vascular Surgery - Estrogen and the Injury Response

血管外科 - 雌激素和损伤反应

• 批准号: 7822191
• 负责人: MICHAEL E MENDELSOHN
• 金额: $ 1.59万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822191
• 关键词: Accounting; Address; Adult; Age; Agonist; Animal Welfare; Animals; ApoE knockout mouse; Apolipoprotein E; Area; Arterial Fatty Streak; Atherosclerosis; Attention; Bibliography; Biology; Blood Pressure; Blood Vessels; Breeding; Cardiology; Cardiovascular system; Caspase; Cells; Clinical Trials; Collaborations; Complex; Conceptions; Confusion; Contractile Proteins; Controlled Study; Coronary; Country; Data; Deposition; Disease; Embryo; Endothelial Cells; Environment; Environmental Impact; Equipment; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Figs - dietary; France; Funding; Gene Expression; Genes; Genomics; Hand; Hormone replacement therapy; Hormones; IACUC; Image; Injury; International; Journals; Knock-out; Knockout Mice; Laboratories; Ligands; Medial; Mediating; Medical center; Menopause; Mesenteric Arteries; Mesentery; Modeling; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Nature; New England; Observational Study; Occupations; Operative Surgical Procedures; Paper; Pathway interactions; Perimenopause; Peripheral; Phenotype; Population; Principal Investigator; Process; Production; Productivity; Progress Reports; Protein Isoforms; Publications; Published Comment; Publishing; Reading; Regulation; Relaxation; Reporting; Research; Research Ethics Committees; Research Institute; Research Personnel; Resistance; Resources; Role; Series; Smooth Muscle Myocytes; Societies; Study models; Suggestion; Tamoxifen; Testing; Text; Therapeutic Agents; Time; Tissues; Vascular Diseases; Vascular Endothelial Cell; Vertebrates; Wild Type Mouse; Woman; Work; abstracting; activating transcription factor; arteriole; cerebrovascular; constriction; design; expiration; hormone therapy; human subject; in vivo; interest; knockout animal; macrophage; mortality; mouse model; neuronal cell body; non-genomic; novel therapeutics; programs; protective effect; response; response to injury; vascular smooth muscle cell proliferation

The role of hormone action and hormone replacement therapy in vascular biology is an area of intense interest, but remains highly controversial. Most investigators now favor the hypothesis that the evolving nature of vascular disease makes critical the timing of initiation of estrogen therapy, with a protective effect seen when women receive estrogen during or soon after menopause, rather than much later. It is now well accepted that estrogen has direct effects on cardiovascular tissues that account for the majority of the protective effects of estrogen against vascular diseases. The direct effects of estrogen on the vasculature are mediated by two ligand-activated transcription factors, estrogen receptors ER1 and ER2. This competitive renewal application builds upon over a decade of research done by the Molecular Cardiology Research Institute in collaboration with the Vascular Surgery Division at Tufts-New England Medical Center, in which we have explored the mechanisms of ER1 and ER2 action in the vasculature using wild type (WT) and ER knockout (ERKO) animals, and a combination of molecular, cellular and vascular models. Work to date has refined the understanding of ER action in the vasculature and supports that ERs mediate both control of vascular tone by estrogen and the protective effects of estrogen on vascular injury and atherosclerosis, in part through regulation of NOS isoforms (eNOS, iNOS) by both genomic and non-genomic pathways. However, studies to date have relied on exploring estrogen effects in mouse models in which an ER is disrupted in the early embryo (whole animal ER knockout mice), so that the ER is deleted from conception in all tissues and cells of the body. The present application proposes to test the mechanistic hypotheses we have evolved over the past decade using exciting new genetically modified mice that are now in hand. These mice, and their tissues and cells, enable the precise deletion of ER1 or ER2 from either EC or VSMC and provide powerful approaches to testing the central hypotheses of this application that vascular endothelial cell ER1 regulates eNOS expression and activity; vascular smooth muscle cell (VSMC) ER1 mediates estrogen inhibition of VSMC proliferation during vascular injury and atherosclerosis; and VSMC ER2 controls genes encoding key contractile proteins regulating VSMC tone. These mechanisms are explored in 3 Specific Aims using intact animals, blood vessels and cells with VSMC- or EC-specific, induced deletions of ER1 or ER2 in studies of the (SA1) role of vascular ER1 and ER2 in the regulation of vascular tone in intact vessels; (SA2) role of vascular ER1 and ER2 in estrogen protection of the vascular injury response in normolipidemic animals; and (SA3) role of vascular ER1 and ER2 in atherosclerosis. These studies are expected to add substantially to our understanding of the molecular and cellular biology of ERs expressed in the blood vessel and vascular physiology, with important impact on the field of women's health and on the development of new therapies for the prevention and treatment of vascular diseases in both women and men.

激素作用和激素替代疗法在血管生物学中的作用是一个非常感兴趣的领域，但仍然存在很大争议。大多数研究人员现在支持这样的假设，即血管疾病的演变性质使得开始雌激素治疗的时机至关重要，当女性在绝经期间或绝经后不久接受雌激素时，而不是更晚时，可以看到保护作用。现在普遍认为雌激素对心血管组织有直接作用，这是雌激素对血管疾病的大部分保护作用的原因。雌激素对血管系统的直接作用由两种配体激活的转录因子，雌激素受体ER 1和ER 2介导。这项竞争性更新申请建立在分子心脏病研究所与塔夫茨新英格兰医学中心血管外科合作进行的十多年研究的基础上，在这些研究中，我们使用野生型（WT）和ER敲除（ERKO）动物以及分子，细胞和血管模型的组合探索了ER 1和ER 2在血管系统中的作用机制。迄今为止的工作已经完善了对ER在血管系统中作用的理解，并支持ER介导雌激素对血管张力的控制以及雌激素对血管损伤和动脉粥样硬化的保护作用，部分通过基因组和非基因组途径调节NOS亚型（eNOS，iNOS）。然而，迄今为止的研究依赖于探索小鼠模型中的雌激素效应，其中ER在早期胚胎中被破坏（整个动物ER敲除小鼠），使得ER在身体的所有组织和细胞中从受孕中被删除。本申请提出使用现在可用的令人兴奋的新的遗传修饰小鼠来测试我们在过去十年中进化的机制假设。这些小鼠及其组织和细胞能够从EC或VSMC中精确缺失ER 1或ER 2，并提供了强有力的方法来测试本申请的中心假设，即血管内皮细胞ER 1调节eNOS表达和活性;血管平滑肌细胞（VSMC）ER 1介导血管损伤和动脉粥样硬化期间VSMC增殖的雌激素抑制; VSMC ER 2控制编码调节VSMC张力的关键收缩蛋白的基因。这些机制在3个特定目的中进行了探索，使用具有VSMC或EC特异性的、诱导的ER 1或ER 2缺失的完整动物、血管和细胞，研究（SA 1）血管ER 1和ER 2在完整血管中调节血管张力的作用;（SA 2）血管ER 1和ER 2在血脂正常动物中雌激素保护血管损伤反应中的作用;（SA 3）血管ER 1和ER 2在动脉粥样硬化中的作用。预计这些研究将大大增加我们对血管和血管生理学中表达的ER的分子和细胞生物学的理解，对女性健康领域以及预防和治疗女性和男性血管疾病的新疗法的开发产生重要影响。