Long Term Implications of Preeclampsia: Role of Obesity vs sFlt-1 Overexpression

先兆子痫的长期影响：肥胖与 sFlt-1 过度表达的作用

基本信息

批准号：
7689212
负责人：
Egle Bytautiene Prewit
金额：
$ 7.55万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7689212
关键词：
Adenoviruses Affect Angiogenic Factor Animal Model Animals Binding Blood Blood Circulation Blood Pressure Blood Vessels C-reactive protein Cardiovascular Diseases Cardiovascular system Cause of Death Cholesterol Clinical Conscious Coronary Arteriosclerosis Coronary heart disease Data Development Diabetes Mellitus Diet Disease Edema Elderly Environmental Risk Factor Epidemiologic Studies Etiology Fatty acid glycerol esters Functional disorder Future Genes Genetic Glucose Goals Health Hepatic Histopathology Human Hyperglycemia Hyperinsulinism Hyperlipidemia Hypertension Hypertriglyceridemia Hypoxia Impairment In Vitro Incidence Insulin Resistance Intervention Investigation Kidney Lead Leptin Life Light Link Liver Dysfunction Measurement Measures Mediating Modeling Morbidity - disease rate Mothers Mus Obesity Organ Outcome Overweight Pathway interactions Patients Placentation Plasma Postpartum Period Pre-Eclampsia Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Prevention strategy Proteinuria Rattus Recording of previous events Relative (related person)Reporting Reproduction Risk Risk Factors Role Saline Screening procedure Severities Sex Characteristics Stroke Symptoms Syndrome Telemetry Testing Time Transducers Transfection Triglycerides United States Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vasoconstrictor Agents Vasodilation Vasodilator Agents Virus Woman angiogenesis base cardiovascular disorder risk cardiovascular risk factor cohort in vivo inflammatory marker insulin sensitivity mortality mouse model normotensive novel offspring overexpression pregnant prevent prospective research study response tool trophoblast vasoactive agent

项目摘要

DESCRIPTION (provided by application): Cardiovascular disease (CVD) is the leading cause of death in women in the United States. Epidemiological studies have demonstrated that preeclampsia could identify women at increased risk to develop hypertension,coronary artery disease, diabetes, and stroke later in life. However, preeclampsia is unlikely to be associated with a single causative factor and shares common pathogenic features with CVD, including endothelial dysfunction, thrombophilic predisposition, alterations in insulin sensitivity, hypertriglyceridemia, and proinflammatory changes. Therefore, some women may have underlying risk factors for CVD that also predispose them to preeclampsia. Obesity is a common risk factor for both. C-reactive protein, a marker for inflammation, is increased in both conditions. Plasma leptin levels are elevated even before preeclampsia is clinically evident, suggesting that the obese gene may be involved. Recent reports support a role for abnormal angiogenesis in the development of preeclampsia. The soluble Flt1 (sFlt1) is the soluble form of the vascular endothelial growth factor (VEGF) receptor 1, which binds VEGF and other angiogenic factors in the circulation, thereby decreasing their action. Based on prior reports, we successfully characterized and refined an animal model of preeclampsia by transfecting mice with an adenovirus carrying sFlt1. This model is characterized by elevated blood pressure, placental hypoxia, vascular, hematological, hepatic, and renal changes in response to overexpression of sFlt1 during pregnancy. We have also followed these animals postpartum. In preliminary experiments performed in mice 6 to 8 months after delivery, we did not find differences in the vascular reactivity in vitro, nor blood pressure in vivo, between mice injected with control virus mFc or saline and mice that had sFlt1-induced preeclampsia. Therefore, we hypothesize that pregnancy complications superimposed on CVD risk factors, such as obesity, lead to the development of long-term adverse changes in the maternal vasculature. To test this hypothesis, we propose the following aims: (1) to determine vascular function in pregnant mice with preexisting obesity, with or without sFlt1-induced preeclampsia, and compare with that in pregnant mice on a regular diet, with or without sFlt1-induced preeclampsia; and (2) to examine the long-term cardiovascular vascular function in mice with or without pre-pregnancy obesity, and with or without sFlt1- induced preeclampsia. Comparison of vascular function in pregnanct and postpartum animals in this model will shed light on the importance of preexisting conditions versus preeclampsia and their interaction in the development of maternal CVD. This model will also provide an experimental tool for investigating mechanisms of CVD and the well established gender differences in health and disease.

描述（由申请提供）：心血管疾病 (CVD) 是美国女性死亡的主要原因。流行病学研究表明，先兆子痫可能会导致女性在以后的生活中患高血压、冠状动脉疾病、糖尿病和中风的风险增加。然而，先兆子痫不太可能与单一致病因素相关，并且与 CVD 具有共同的致病特征，包括内皮功能障碍、血栓形成倾向、胰岛素敏感性改变、高甘油三酯血症和促炎性变化。因此，一些女性可能存在心血管疾病的潜在危险因素，这些因素也使她们容易患先兆子痫。肥胖是两者的共同危险因素。 C反应蛋白（炎症标志物）在这两种情况下都会增加。甚至在先兆子痫出现临床症状之前，血浆瘦素水平就升高，这表明肥胖基因可能参与其中。最近的报告支持异常血管生成在先兆子痫的发展中的作用。可溶性 Flt1 (sFlt1) 是血管内皮生长因子 (VEGF) 受体 1 的可溶形式，可结合循环中的 VEGF 和其他血管生成因子，从而降低其作用。根据之前的报道，我们通过用携带 sFlt1 的腺病毒转染小鼠，成功地表征和完善了先兆子痫的动物模型。该模型的特点是妊娠期间 sFlt1 过度表达导致血压升高、胎盘缺氧、血管、血液、肝脏和肾脏发生变化。我们还在产后跟踪这些动物。在分娩后 6 至 8 个月的小鼠中进行的初步实验中，我们没有发现注射对照病毒 mFc 或盐水的小鼠与患有 sFlt1 诱导的先兆子痫的小鼠之间的体外血管反应性和体内血压存在差异。因此，我们假设妊娠并发症与肥胖等心血管疾病危险因素相叠加，会导致母体脉管系统发生长期不利变化。为了检验这一假设，我们提出以下目标：（1）确定先前存在肥胖、伴或不伴 sFlt1 诱导的先兆子痫的妊娠小鼠的血管功能，并与常规饮食、伴或不伴 sFlt1 的妊娠小鼠进行比较。诱发先兆子痫； (2)检查有或没有孕前肥胖以及有或没有sFlt1诱导的先兆子痫的小鼠的长期心血管功能。该模型中妊娠和产后动物血管功能的比较将揭示先前存在的疾病与先兆子痫的重要性以及它们在母体心血管疾病发展中的相互作用。该模型还将提供一个实验工具，用于研究心血管疾病的机制以及健康和疾病方面已确立的性别差异。