Anti-Angiogenic Preeclamptic Milieu Impairs Infant Lung and Vascular Development

描述（由申请人提供）：先兆子痫以产妇高血压和全身内皮血管功能障碍为特征，发生在3-8%的妊娠中，并与显著的新生儿发病率相关。在早产婴儿中，先兆子痫与支气管肺发育不良（BPD）的高风险以及其他系统性并发症的风险增加独立相关。即使是子痫前期妇女所生的晚期早产儿，与正常妊娠相比，也有更高的呼吸系统发病率、更高的呼吸窘迫综合征发生率、更高的新生儿重症监护病房入院率、更长的新生儿住院时间和更高的呼吸支持需求。子痫前期的发病机制与可溶性血管内皮生长因子（VEGF）受体-1 （sFlt-1）的过量产生有关，该受体-1抑制VEGF信号传导。过量的sFlt-1在母体血清，以及在羊水，与子痫前期的严重程度相关。此外，妊娠合并子痫前期新生儿脐带血中sFlt-1升高，VEGF水平降低，血管生成循环祖细胞（CPCs）的数量和功能下降。因此，子痫前期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，孕妇的抗血管生成环境与先兆子痫损害肺和血管发育的婴儿。我们研究的总体目标将通过以下具体目的来实现：SA #1: A)确定先兆子痫是否会损害婴儿肺部发育，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血管生成环境有关，如CPCs减少、CPC：非CPC比值降低、VEGF降低、sFlt-1升高。SA #2: A)确定子痫前期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。B)检查全身性血管功能受损是否与脐带血血管生成环境有关，如CPCs减少、CPC：非CPC比值降低、VEGF降低和sFlt-1升高。

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.