Anti-Angiogenic Preeclamptic Milieu Impairs Infant Lung and Vascular Development

描述(申请人提供)：先兆子痫，其特征是母体高血压和全身血管内皮功能障碍，发生在3-8%的怀孕，并与显著的新生儿发病率有关。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。即使是先兆子痫妇女所生的晚期早产儿，与正常血压的孕妇相比，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住院率、更长的新生儿住院时间以及更多的呼吸支持需求。子痫前期的发病机制与可溶性血管内皮生长因子受体-1(sFlt-1)的过度产生有关，sFlt-1抑制了血管内皮生长因子信号转导。孕妇血清和羊水中sFlt-1的过量与子痫前期的严重程度有关。此外，妊娠合并子痫前期的新生儿脐带出血增加了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会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体内的抗血管生成环境损害了婴儿的肺和血管发育。我们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，表现为肺弥散能力和呼吸道功能下降。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：Non CPC比率降低、VEGF减少和sFlt-1增加。SA#2：a)确定先兆子痫是否损害婴儿的全身血管功能，表现为毛细血管密度降低、血管反应性增强和血压升高。B)检查全身血管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/Non CPC比率降低、VEGF减少和sFlt-1增加。

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.