Anti-Angiogenic Preeclamptic Milieu Impairs Infant Lung and Vascular Development

抗血管生成先兆子痫环境损害婴儿肺和血管发育

基本信息

批准号：
9144430
负责人：
Laura S Haneline
金额：
$ 64.81万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144430
关键词：
Address Admission activity Adolescent Adult Air Alveolar Alveolus Amniotic Fluid Angiogenic Factor Animal Model Autopsy Biological Markers Biology Blood Blood Pressure Blood Vessels Blood capillaries Bronchopulmonary Dysplasia Carbon Monoxide Cells Cellular biology Child Childhood Clinical Clinical Investigator Complex Data Development Diabetes Mellitus Diffusion Discipline of obstetrics Environment Equilibrium Fetus Flow Cytometry Gases Growth Health Hospitalization Human Hypertension Infant Life Lung Lung diseases Measures Methodology Modeling Morbidity - disease rate Mothers Neonatal Neonatology Pathogenesis Physiological Physiology Pre-Eclampsia Pregnancy Premature Infant Process Pulmonary Diffusing Capacity Rattus Respiratory physiology Risk Rodent Model Role Severities Signal Transduction Spirometry Stem cells Techniques Translating Umbilical Cord Blood Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Woman angiogenesis capillary density endothelial dysfunction fetal high risk infant of diabetic mother lung development maternal hypertension maternal serum mouse model neonatal morbidity new therapeutic target normotensive novel pregnant respiratory respiratory distress syndrome stem vascular endothelial dysfunction

项目摘要

DESCRIPTION (provided by applicant): Preeclampsia, which is characterized by maternal hypertension and systemic endothelial vascular dysfunction, occurs in 3-8% of pregnancies and is associated with significant neonatal morbidities. Among infants born premature, preeclampsia is independently associated with a high risk of bronchopulmonary dysplasia (BPD), as well as an increased risk of other systemic complications. Even late preterm infants born to preeclamptic women have higher respiratory morbidity, greater rates of respiratory distress syndrome, increased rates of NICU admission, longer neonatal hospitalization, and increased respiratory support needs compared to normotensive pregnancies. The pathogenesis of preeclampsia relates to overproduction of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which inhibits VEGF signaling. The excess sFlt-1 in maternal serum, as well as in amniotic fluid, correlates with the severity of preeclampsia. In addition, neonatal cord bloo from pregnancies complicated by preeclampsia has increased sFlt-1, reduced VEGF levels, and decreased numbers and function of angiogenic circulating progenitor cells (CPCs). Therefore, the anti-angiogenic environment of preeclampsia likely impairs angiogenic processes in the fetus and infant. We hypothesize that the anti-angiogenic environment in pregnant mothers with preeclampsia impairs pulmonary and vascular development in the infant. The overall objective of our study will be achieved in the following Specific Aims: SA #1: A) Determine whether preeclampsia impairs infant lung development, as evidenced by reduced pulmonary diffusion capacity and airway function. B) Examine whether impaired lung function is related to the angiogenic environment in cord blood, as evidenced by fewer CPCs, decreased CPC: nonCPC ratio, reduced VEGF, and increased sFlt-1. SA #2: A) Determine whether preeclampsia impairs infant systemic vascular function, as evidenced by reduced capillary density, increased vasoreactivity, and increased blood pressure. B) Examine whether impaired systemic vascular function is related to the angiogenic environment in cord blood, as evidenced by fewer CPCs, reduced CPC: nonCPC ratio, reduced VEGF, and increased sFlt-1.

描述（由申请人提供）：先兆子痫的特征是产妇高血压和全身内皮血管功能障碍，发生在 3-8% 的妊娠中，并且与显着的新生儿发病率相关。在早产儿中，先兆子痫与支气管肺发育不良（BPD）的高风险以及其他全身并发症的风险增加独立相关。与血压正常的妊娠相比，即使是先兆子痫妇女所生的晚期早产儿，其呼吸系统发病率也更高，呼吸窘迫综合征的发生率更高，NICU 入住率更高，新生儿住院时间更长，呼吸支持需求也更高。先兆子痫的发病机制与可溶性血管内皮生长因子 (VEGF) 受体-1 (sFlt-1) 的过量产生有关，该受体会抑制 VEGF 信号传导。母体血清和羊水中过量的 sFlt-1 与先兆子痫的严重程度相关。此外，妊娠并发先兆子痫的新生儿脐带血增加了 sFlt-1，降低了 VEGF 水平，并降低了血管生成循环祖细胞 (CPC) 的数量和功能。因此，先兆子痫的抗血管生成环境可能损害胎儿和婴儿的血管生成过程。我们假设患有先兆子痫的孕妇的抗血管生成环境会损害婴儿的肺部和血管发育。我们研究的总体目标将通过以下具体目标实现： SA #1：A) 确定先兆子痫是否损害婴儿肺部发育，如肺弥散能力和气道功能降低所证明的那样。 B) 检查肺功能受损是否与脐带血中的血管生成环境有关，如 CPC 减少、CPC：非 CPC 比率降低、VEGF 减少和 sFlt-1 增加所证明。 SA #2：A) 确定先兆子痫是否损害婴儿全身血管功能，如毛细血管密度降低、血管反应性增加和血压升高所证明的那样。 B) 检查受损的全身血管功能是否与脐带血中的血管生成环境有关，如 CPC 减少、CPC：非 CPC 比率降低、VEGF 减少和 sFlt-1 增加所证明。