Endothelial Function in a Model of IUGR Induced by Uterine Space Restriction

子宫空间限制引起的 IUGR 模型中的内皮功能

• 批准号: 8639270
• 负责人: RONALD R MAGNESS
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639270
• 关键词: Address; Adult; Angiogenic Factor; Angiotensin II; Animals; Assisted Reproductive Technology; Attenuated; Barker Hypothesis; Baroreflex; Birth Weight; Blood Pressure; Blood Vessels; Blood Volume; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Contracts; Development; Disease; Dyslipidemias; Environment; Essential Hypertension; Exhibits; Exposure to; FGF2 gene; Fetal Growth; Fetal Growth Retardation; Fetus; Fibroblast Growth Factor 2; Gender; Genotype; Growth; Health; Human; Hypertension; In Vitro; Intervention; Kidney; Lead; Life; Maintenance; Maternal-Fetal Exchange; Mediating; Metabolic; Modeling; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Onset of illness; Outcome; Oxygen; Perfusion; Perinatal Exposure; Phenotype; Physiological; Physiological Processes; Placenta; Placental Insufficiency; Predisposition; Pregnancy; Process; Regulation; Renin; Renin-Angiotensin System; Signal Transduction; Stress; Testing; Therapeutic Intervention; Third Pregnancy Trimester; Vascular Endothelial Growth Factors; Vasodilation; Woman; angiogenesis; base; epidemiologic data; fetal; hypercholesterolemia; in utero; in vivo; male; novel; offspring; postnatal; prevent; programs; public health relevance; response; young adult

DESCRIPTION (provided by applicant): Pregnancy is associated with substantial cardiovascular adaptations including dramatically increased maternal uterine blood flow (UBF) and fetoplacental blood flows for fetal nutrient delivery. Vasodilatation and angiogenesis are the mechanisms normally controlling maternal fetal perfusion, but perfusion is reduced in pregnancies complicated by intrauterine growth restriction (IUGR). Based on the Barker hypothesis, when reaching adulthood, these IUGR/small birth weight babies exhibit a host of adult onset diseases, including hypertension and its associated morbidity. It is of great importance to understand the causes and sequelae of IUGR. Limited uterine space in multi-fetal gestations and uterine anomalies cause IUGR from uterine and placental insufficiency. We developed a novel surgically-created ovine uterine space restriction model that partially maintained UBF with placental vasculature adaptations to sustain viable fetuses with asymmetric IUGR. We propose to utilize this model to study numerous physiological processes involved in placental, fetal, and postnatal vascular development. We will test the hypotheses that during uterine space restriction, both the maternal and fetal components of the placenta (uteroplacental/fetoplacental interface) and specifically their vasculatures initially adapt to preserve sustained fetal growth through partial maintenance of rises in uterine and fetal placental blood flows (Aim I) via NO-mediated vasodilatory (Aim II) as well as VEGF- and FGF2- mediated angiogenesis (Aim III) via cell and molecular signaling mechanisms. However, with growth arrest after 0.9 gestation, both vasodilatory and angiogenic mechanisms are inadequate, leading to placental insufficiency with consequent cessation of fetal growth velocity. Because the vascular adaptations ultimately define the postnatal cardiovascular phenotype of IUGR offspring, we will test the hypothesis that the outcome is postnatal programming of hypertension (Aim IV) with dysfunctional renal development, RAS activation, and altered blood volume and pressor studies in yearling lambs. These aims will address vascular adaptation to decreased uterine space through physiological, signaling, and molecular mechanisms of vasodilatation and angiogenesis.

描述（由申请人提供）：妊娠与实质性心血管适应相关，包括母体子宫血流量（UBF）和胎儿胎盘血流量显著增加，用于胎儿营养输送。血管舒张和血管生成是正常控制母体胎儿灌注的机制，但在妊娠合并宫内生长受限（IUGR）时灌注减少。根据Barker假说，当这些IUGR/低出生体重婴儿达到成年时，表现出许多成人发病疾病，包括高血压及其相关的发病率。了解胎儿宫内发育迟缓的病因及后遗症具有重要意义。多胎妊娠子宫腔狭窄和子宫异常是子宫和胎盘功能不全引起IUGR的原因。我们开发了一种新的人工创建的绵羊子宫空间限制模型，部分维持UBF与胎盘血管适应，以维持不对称IUGR的活胎。我们建议利用这个模型来研究胎盘，胎儿和出生后血管发育所涉及的许多生理过程。我们将检验在子宫空间受限期间，胎盘的母体和胎儿成分（子宫胎盘/胎儿胎盘界面），特别是它们的血管系统最初通过NO介导的血管舒张（Aim II）以及VEGF和FGF 2介导的血管生成（Aim III），通过部分维持子宫和胎儿胎盘血流量（Aim I）的上升，适应维持持续的胎儿生长。通过细胞和分子信号机制。然而，在妊娠0.9个月后生长停止，血管舒张和血管生成机制都不充分，导致胎盘功能不全，随后胎儿生长速度停止。由于血管适应最终定义了出生后的心血管表型IUGR后代，我们将测试的假设，结果是出生后编程高血压（目的IV）与肾功能障碍的发展，RAS激活，改变血容量和升压研究在一岁羔羊。这些目标将通过血管舒张和血管生成的生理、信号和分子机制来解决血管适应子宫空间减少的问题。