Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang, China.
Department of Neonatology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, China.
Microvasc Res. 2022 Mar;140:104308. doi: 10.1016/j.mvr.2021.104308. Epub 2022 Jan 4.
Intrauterine growth restriction (IUGR) is associated with increased perinatal mortality and morbidity, and plays an important role in the development of adult cardiovascular diseases. This study brings forward a hypothesis that Human umbilical vein endothelial cells (HUVECs) from IUGR newborns present dysfunctions and varying changes of signaling pathways as compared to the Control group. Similar pathways may also be present in pulmonary or systemic vasculatures. HUVECs were derived from newborns. There were three groups according to the different fetal origins: normal newborns (Control), IUGR from poor maternal nutrition (IUGR1), and pregnancy-induced hypertension (IUGR2). We found that IUGR-derived HUVECs showed a proliferative phenotype compared to those from normal subjects. Interestingly, two types IUGR could cause varying degrees of cellular dysfunction. Meanwhile, the Notch1 signaling pathway showed enhanced activation in the two IUGR-induced HUVECs, with subsequent activation of Akt or extracellular signal regulated protein kinases1/2 (ERK1/2). Pharmacological inhibition or gene silencing of Notch1 impeded the proliferative phenotype of IUGR-induced HUVECs and reduced the activation of ERK1/2 and AKT. In summary, elevated Notch1 levels might play a crucial role in IUGR-induced HUVECs disorders through the activation of ERK1/2 and AKT. These pathways could be potential therapeutic targets for prevention of the progression of IUGR associated diseases later in life.
胎儿宫内生长受限（IUGR）与围产期死亡率和发病率增加有关，并在成人心血管疾病的发展中起重要作用。本研究提出了一个假设，即与对照组相比，来自 IUGR 新生儿的人脐静脉内皮细胞（HUVEC）存在功能障碍和信号通路的不同变化。类似的途径也可能存在于肺或全身脉管系统中。HUVEC 来源于新生儿。根据不同的胎儿来源，有三组：正常新生儿（对照组）、营养不良引起的 IUGR（IUGR1）和妊娠高血压引起的 IUGR（IUGR2）。我们发现，与正常受试者相比，IUGR 来源的 HUVEC 表现出增殖表型。有趣的是，两种类型的 IUGR 均可导致不同程度的细胞功能障碍。同时，Notch1 信号通路在两种 IUGR 诱导的 HUVEC 中表现出增强的激活，随后激活 Akt 或细胞外信号调节蛋白激酶 1/2（ERK1/2）。Notch1 的药理学抑制或基因沉默抑制了 IUGR 诱导的 HUVEC 的增殖表型，并降低了 ERK1/2 和 AKT 的激活。总之，Notch1 水平的升高可能通过激活 ERK1/2 和 AKT 在 IUGR 诱导的 HUVEC 紊乱中起关键作用。这些途径可能是预防 IUGR 相关疾病在以后生活中进展的潜在治疗靶点。
