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

基本信息

批准号：
8119435
负责人：
Margaret Markiewicz
金额：
$ 11.82万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119435
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

项目摘要

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）：血管生成是从预先存在的毛细血管或小静脉形成新血管的过程。据报道，衰老组织中的这一过程受到损害。随着衰老而发生的血管生成的变化已在分子、细胞和生理调节水平上得到记录。类固醇激素是已被证明对新血管形成过程有影响的因素之一。雌激素是类固醇激素之一，被认为可以促进新血管形成。然而，雌激素对内皮细胞功能和血管生成作用的调节机制尚不完全清楚。雌激素的作用是通过雌激素受体介导的 ? （ER？）和/或雌激素受体？（呃？？）。在我们的研究中，我们利用女性 ER 研究了雌激素受体在新血管形成过程中的作用。和急诊室？？基因敲除小鼠。我们的初步数据表明，ER 和 ER 中的皮肤微血管系统均受到损害。 -/- 和急诊室？ -/- 老鼠。此外，从ERα分离的内皮细胞中，一些参与血管稳定调节的基因（例如PDGFB、VE-cadherin、N-cadherin）的mRNA水平下调。 -/- 老鼠。此外，我们观察到 ER α-/- 小鼠中胶原蛋白合成增加，而 ERα-/- 小鼠中胶原蛋白合成减少。 -/- 老鼠。有趣的是，两种蛋白多糖，Lumican和Decorin在ER??皮肤中增加。 -/- 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的不同影响。我们假设 ER??和/或急诊室？在按时间顺序衰老过程中调节介导血管稳态的基因程序中发挥重要作用。为了解决我们的假设，我们提出了三个目标。在具体目标 1 中，我们将表征 ER 中的皮肤微血管系统？ -/-，急诊室？？ -/- 和 12ERKO 小鼠。由于细胞外基质在血管网络中起着重要作用，我们将在具体目标2中分析小鼠体内基质相关基因。这些分析将使我们能够确定ER??的影响。和急诊室？？关于这些动物的 ECM 生产。在具体目标3中，我们将确定ER??的机制。和急诊室？？使用 3D 共培养系统在体外研究内皮细胞和成纤维细胞之间的相互作用。根据我们初步的体内阵列数据，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显着减少，这可能是通过 ER?? 调节的。和/或急诊室？？这些研究将使我们更好地了解雌激素受体在按时间顺序衰老过程中调节微血管系统中的作用。公共卫生相关性：血管老化伴内皮细胞功能受损，导致血管生成改变，被认为是 CVD 病因学的关键因素。此外，与年龄相关的心脑血管疾病是老年妇女的主要公共卫生问题。 60-79 岁男性和女性心血管疾病（CVD：中风、高血压、心力衰竭）的患病率约为 73%。然而，79 岁以上的女性 (~86%) 高于男性 (~80%) {(NHANES: 2005-6)-来源 NCH、NHLBI}。最近发表的数据显示，心脑血管疾病分别是65岁以上人群的第一和第三大死因（发病率和死亡率：2007年图表书NHLBI）。此外，66-85 岁人群的发病率增加了 32-48%。我们相信，拟议的小鼠模型中 ER1 或/和 ER2 缺陷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。