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

• 批准号: 9274355
• 负责人: Laura S Haneline
• 金额: $ 65.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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/9274355
• 关键词: Address; Admission activity; Adolescent; Adult; Air; Alveolar; Amniotic Fluid; Angiogenesis Inhibition; 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; Diffuse; Diffusion; Discipline of obstetrics; Environment; Equilibrium; Fetus; Flow Cytometry; Gases; Growth; Health; Hospitalization; Human; Hypertension; Impairment; 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; public health relevance; respiratory; respiratory distress syndrome; stem; translational scientist; vascular endothelial dysfunction

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，其特征是母体高血压和全身性内皮血管功能障碍，发生在3-8%的妊娠中，并与显著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性并发症的风险增加独立相关。与血压正常的孕妇相比，即使是先兆子痫孕妇所生的晚期早产儿也有更高的呼吸道发病率、更高的呼吸窘迫综合征发生率、更高的NICU入院率、更长的新生儿住院时间和更高的呼吸支持需求。先兆子痫的发病机制与抑制VEGF信号传导的可溶性血管内皮生长因子（VEGF）受体-1（sFlt-1）的过度产生有关。母体血清以及羊水中过量的sFlt-1与先兆子痫的严重程度相关。此外，妊娠合并先兆子痫的新生儿脐带血增加了sFlt-1，降低了VEGF水平，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。我们推测，先兆子痫孕妇的抗血管生成环境损害了婴儿的肺和血管发育。本研究的总体目标将在以下具体目标中实现：SA #1：A）确定先兆子痫是否损害婴儿肺发育，如肺扩散能力和气道功能降低所证明的。B）检查受损的肺功能是否与脐带血中的血管生成环境相关，如通过较少的CPC、降低的CPC：非CPC比率、降低的VEGF和增加的sFlt-1所证明的。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。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相关，如通过较少的CPC、降低的CPC：非CPC比率、降低的VEGF和增加的sFlt-1所证明的。