Regulation of vasculature by estrogen receptors during aging in mouse models

小鼠模型衰老过程中雌激素受体对脉管系统的调节

• 批准号: 8508772
• 负责人: Margaret Markiewicz
• 金额: $ 12.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508772
• 关键词: Address; Age; Aging; Angiogenesis Modulating Agents; Animals; Blood Vessels; Blood capillaries; Books; Caliber; Cardiovascular Diseases; Cause of Death; Cell Communication; Cell physiology; Cells; Cerebral Ischemia; Cerebrovascular Disorders; Coculture Techniques; Collagen; Complex; Congestive Heart Failure; Control Animal; Coronary Arteriosclerosis; Cytoskeleton; Data; Dermal; Desmin; Disease; Elderly woman; Endothelial Cells; Estrogen Receptors; Estrogens; Etiology; Extracellular Matrix; Extracellular Matrix Degradation; Female; Fibroblasts; Functional disorder; Future; Genes; Heart failure; Homeostasis; Hypertension; Impairment; In Vitro; Injection of therapeutic agent; Knockout Mice; Lead; Leucine; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Mus; N-Cadherin; National Health and Nutrition Examination Survey; National Heart, Lung, and Blood Institute; PDGFB gene; Pericytes; Peripheral Vascular Diseases; Physiological; Play; Prevalence; Process; Production; Proteoglycan; Public Health; Publishing; Regulation; Reporting; Role; Skin; Smooth Muscle Actin Staining Method; Source; Stroke; System; Testing; Tissues; Tube; age related; aged; angiogenesis; base; cadherin 5; capillary; cell motility; decorin; fluorescein isothiocyanate dextran; in vivo; insight; junctional adhesion molecule; lumican; male; mortality; mouse model; neovascularization; novel therapeutic intervention; programs; public health relevance; steroid hormone; venule

DESCRIPTION (provided by applicant): Angiogenesis is a process of new vessel formation from pre existing capillaries or venules. It has been reported that this process is impaired in aged tissues. The changes in angiogenesis that occur with aging have been documented at the molecular, cellular, and physiological levels of regulation. The steroid hormones are among the factors that have been shown to have influence on the neovascularization process. Estrogen is one of the steroid hormones which has been suggested to promote new vessel formation. However, regulatory mechanisms underlying the action of estrogen on endothelial cell function and angiogenesis are not fully understood. The action of estrogen is mediated through the estrogen receptor ? (ER??) and/or estrogen receptor ? (ER??). In our study we investigated the role of estrogen receptors in the process of new vessel formation using female ER?? and ER?? knockout mice. Our preliminary data have demonstrated an impairment of skin microvasculature in both ER?? -/- and ER?? -/- mice. Moreover, mRNA levels of several genes involved in the regulation of vessels stabilization such as PDGFB, VE-cadherin, N-cadherin were downregulated in the endothelial cells isolated from ER ? -/- mice. Furthermore, we observed increased collagen synthesis in the ER ?-/- mice, while a decrease was observed in ER?? -/- mice. Interestingly, two proteoglycans, Lumican and Decorin were increased in the skin of ER?? -/- mice, while their decrease was observed in the skin of ER?? -/- mice. These results may indicate an opposite regulation of these ECM components by estrogen receptors suggesting a differential influence on neovascularization process. We hypothesize that ER?? and/or ER?? play an essential role in regulating gene programs mediating vessel homeostasis during chronological aging. To address our hypothesis, we have proposed three aims. In specific aim 1, we will characterize the skin microvasculature in ER?? -/-, ER?? -/- and 12ERKO mice. Since the extra-cellular matrix plays an important role in the vascular network, we will analyze the matrix related genes in mice in vivo in specific aim 2.These analyses will allow us to determine the effects of ER?? and ER?? on ECM production in these animals. In specific aim 3, we will determine the mechanism of ER?? and ER?? on the interaction between endothelial cells and fibroblasts in vitro, using 3D co-culture system. Based on our preliminary in vivo array data we found a significant decrease of adhesion and junction molecules responsible for the cell-cell contact and cell-cell interaction, which may be modulated by ER?? and/or ER??. These studies will allow us a better understanding of the role of estrogen receptors in the regulation of microvasculature during chronological aging. PUBLIC HEALTH RELEVANCE: Vascular aging with impaired endothelial cell function, which leads to altered angiogenesis, is recognized as key factor in the etiology of CVD. Moreover, age related cardiovascular and cerebrovascular diseases represent a major public health concern for elderly women. The prevalence of cardiovascular diseases (CVD: Stroke, hypertension, heart failure) in males and females was ~73% at age 60-79. However, it was higher in females (~86%) than in males (~80%) at age>79 {(NHANES: 2005-6)-source NCH, NHLBI}. Recently published data have shown that cardiovascular and cerebrovascular diseases were the first and third leading cause of death for those of age >65 respectively (Morbidity & Mortality: 2007 Chart Book NHLBI). Furthermore, morbidity increased 32- 48% for those 66-85yrs of age. We believe that the proposed study of ER1 or/and ER2 deficiency in the mouse model will elucidate the mechanism of altered angiogenesis. This may lead to future discovery of a new therapeutic intervention for cardiovascular and cerebrovascular diseases.

描述(申请人提供)：血管生成是指从原有的毛细血管或小静脉形成新的血管的过程。据报道，这一过程在老化的组织中受到损害。随着年龄的增长，血管生成的变化已经在分子、细胞和生理水平上得到了证实。类固醇激素是已被证明对新生血管过程有影响的因素之一。雌激素是类固醇激素之一，被认为可以促进新生血管的形成。然而，雌激素对内皮细胞功能和血管生成的调控机制尚不完全清楚。雌激素的作用是通过雌激素受体介导的？(呃？？)和/或雌激素受体？(呃？？)。在我们的研究中，我们研究了雌激素受体在女性ER新血管形成过程中的作用。那急诊室呢？基因敲除老鼠。我们的初步数据显示，ER？-/-和ER？-/-小鼠的皮肤微血管都受到了损害。此外，在分离的ER？/-小鼠内皮细胞中，PDGFB、VE-cadherin、N-cadherin等参与血管稳定调控的几个基因的mRNA水平下调。此外，我们观察到ER？-/-小鼠的胶原合成增加，而ER？-/-小鼠的胶原合成减少。有趣的是，在ER？？-/-小鼠的皮肤中，Lumcan和Decorin两种蛋白多糖增加，而在ER？？-/-小鼠的皮肤中观察到它们的减少。这些结果可能表明雌激素受体对这些ECM成分的相反调节，表明对新生血管过程的不同影响。我们假设急诊室？？和/或急诊室？？在调节基因程序中发挥重要作用，在慢性衰老过程中调节血管内环境平衡。为了解决我们的假设，我们提出了三个目标。在特定的目标1中，我们将描述ER？？-/-、ER？-/-和12ERKO小鼠的皮肤微血管结构。鉴于细胞外基质在血管网络中的重要作用，我们将有针对性地对小鼠体内的基质相关基因进行分析。这些分析将使我们能够确定ER？？那急诊室呢？在这些动物身上产生细胞外基质。在具体目标3中，我们将确定ER的机制？？那急诊室呢？采用3D共培养系统，研究血管内皮细胞与成纤维细胞的体外相互作用。基于我们在体内的初步阵列数据，我们发现负责细胞-细胞接触和细胞-细胞相互作用的黏附和连接分子显著减少，这可能受内质网？？和/或急诊室？？这些研究将使我们更好地了解雌激素受体在慢性衰老过程中微血管调节中的作用。 公共卫生相关性：血管老化与内皮细胞功能受损，导致血管生成改变，是公认的心血管疾病病因学的关键因素。此外，与年龄有关的心脑血管疾病是老年妇女的主要公共卫生问题。男性和女性的心血管疾病(心血管疾病：中风、高血压、心力衰竭)的患病率在60-79岁之间为~73%。然而，在79岁时，女性(~86%)高于男性(~80%)。最近公布的数据显示，心血管疾病和脑血管疾病分别是65岁和65岁人群的第一和第三大死因(发病率和死亡率：2007年图表手册NHLBI)。此外，在66-85岁的人群中，发病率增加了32-48%。我们相信，对ER1或/和ER2缺陷的小鼠模型的研究将阐明血管生成改变的机制。这可能会导致未来发现一种新的心脑血管疾病治疗干预措施。