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（由申请人提供）：血管生成是从现有毛细血管或静脉前的新血管形成的过程。据报道，这一过程在老年组织中受到损害。衰老发生的血管生成的变化已记录在分子，细胞和生理调节水平上。类固醇激素是已证明对新血管化过程影响的因素之一。雌激素是一种类固醇激素之一，该激素被认为促进新血管形成。但是，尚不完全了解雌激素对内皮细胞功能和血管生成作用的调节机制。雌激素的作用是通过雌激素受体介导的？ （ER ??）和/或雌激素受体？ （er ??）。在我们的研究中，我们研究了雌激素受体在使用雌性ER的新血管形成过程中的作用？和er ??淘汰老鼠。我们的初步数据表明，这两种ER的皮肤微脉管系统都受损？ - / - 和er ?? - / - 老鼠。此外，在调节血管稳定的几个基因的mRNA水平，例如PDGFB，VE-钙粘着蛋白，N-钙粘着蛋白在从ER分离的内皮细胞中下调？ - / - 老鼠。此外，我们观察到ER？/ - 小鼠中胶原蛋白的合成增加，而在ER中观察到了降低？ - / - 老鼠。有趣的是，在ER的皮肤中增加了两个蛋白聚糖，Lumican和Decorin？ - / - 小鼠，而在ER的皮肤中观察到它们的减少？ - / - 老鼠。这些结果可能表明通过雌激素受体对这些ECM成分的相反调节表明对新血管形成过程产生差异影响。我们假设那个ER？和/或ER ??在调节年代衰老期间介导血管稳态的基因程序中起着至关重要的作用。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，我们将表征ER中的皮肤微脉管系统？ - / - ，er ?? - / - 和12erko小鼠。由于细胞外基质在血管网络中起重要作用，因此我们将在特定目标中分析体内小鼠的基因相关基因。这些分析将使我们能够确定ER的影响？和er ??这些动物的ECM生产。在特定的目标3中，我们将确定ER的机制？和er ??关于使用3D共培养系统，在体外内皮细胞与成纤维细胞之间的相互作用。基于我们的初步体内阵列数据，我们发现负责细胞细胞接触和细胞 - 细胞相互作用的粘附和连接分子的显着降低，这可能是由ER调节的？和/或er ??。 这些研究将使我们可以更好地了解雌激素受体在年代老化过程中微脉管系统调节中的作用。 公共卫生相关性：内皮细胞功能受损的血管衰老，导致血管生成改变，被认为是CVD病因的关键因素。此外，与年龄相关的心血管和脑血管疾病是老年妇女的主要公共卫生问题。在60-79岁时，男性和女性的心血管疾病患病率（CVD：中风，高血压，心力衰竭）约为73％。但是，女性（约86％）的年龄高于男性（约80％）> 79 {（NHANES：2005-6）-Source NCH，NHLBI}。最近发表的数据表明，心血管和脑血管疾病分别是年龄> 65岁的第一个和第三大死亡原因（发病率与死亡率：2007年图表NHLBI）。此外，那66-85岁的年龄增长了32-48％。我们认为，小鼠模型中提出的对ER1或/和ER2缺乏症的研究将阐明改变血管生成的机制。这可能会导致未来发现针对心血管和脑血管疾病的新治疗干预措施。