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（由应用提供）：心血管疾病（CVD）是美国妇女的主要死亡原因。流行病学研究表明，先兆子痫可以识别出患有高血压，冠状动脉疾病，糖尿病和中风的女性，后来生活。然而，先兆子痫不太可能与单个病因因素相关，并与CVD共享常见的致病性特征，包括内皮功能障碍，血栓形成倾向，硫蛋白敏感性的改变，高甘油酸酯症和促症状的变化。因此，一些妇女可能具有CVD的潜在危险因素，这也使她们倾向于先兆子痫。肥胖是两者的常见危险因素。在两种情况下，C反应蛋白是一种炎症的标志物都增加了。血浆瘦素水平甚至在先兆子痫在临床上显而易见，这表明可能涉及肥胖基因。最近的报告支持异常血管生成在先兆子痫发展中的作用。可溶性FLT1（SFLT1）是血管内皮生长因子（VEGF）受体1的可溶形式，它在循环中结合了VEGF和其他血管生成因子，从而降低了其作用。根据先前的报道，我们通过用携带SFLT1的腺病毒转染小鼠来成功地表征并完善了子痫前期动物模型。该模型的特征是血压升高，胎盘缺氧，血管，血液学，肝和肾脏变化，以响应于怀孕期间SFLT1的过表达。我们还跟随这些动物产后。在分娩后6至8个月中在小鼠中进行的初步实验中，我们在体外的血管反应性，体内或体内血压没有差异，在注射对照病毒MFC或盐水和盐水和小鼠的小鼠之间没有SFLT1诱导的prececlampsia的差异。因此，我们假设怀孕并发症叠加在CVD危险因素（例如肥胖）上，导致孕产妇脉管系统的长期不良变化的发展。为了检验这一假设，我们提出以下目的：（1）确定肥胖症患者的血管功能，有或没有SFLT1诱导的先兆子痫，并在常规饮食中与孕妇在孕妇中的血管功能，有或没有SFLT1诱导的先前症状。（2）检查具有或没有孕前肥胖症的小鼠的长期心血管血管功能，以及有或没有SFLT1诱导的先兆子痫。该模型中怀孕和产后动物血管功能的比较将揭示出存在疾病的重要性与先兆子痫的重要性及其在母体CVD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CVD的机制以及健康和疾病方面的性别差异。