During pregnancy, women face many pregnancy complications that may endanger their physical condition and fetal health, including glucose intolerance. Previous studies have found that in order to maximize the nutritional needs of the fetus in late pregnancy, pregnant women may develop progressive insulin resistance to reduce their own nutritional and energy consumption [1,2]. However, excessive fat and sugar intake caused by an unbalanced diet often leads to physiological insulin resistance deterioration, glucose tolerance impairment, and even maternal gestational hypertension, preeclampsia, and diabetes. Enhanced maternal fat deposition and obesity during pregnancy are associated with abnormal birth weight and an increased risk of metabolic and cardiovascular diseases for offspring in later life [3]. In addition, other and our previous studies have confirmed that the offspring of mothers with poor glucose tolerance during pregnancy often fail to reach the development level of normal offspring and are even more vulnerable to diseases, such as growth retardation, metabolic syndrome, and diabetes [4], [5], [6], [7].

It is worth noting that the occurrence of insulin resistance during pregnancy is closely bound up with placental growth and development. Insulin resistance in pregnant women has emerged since placental formation and aggravated with the prolongation of gestational weeks, but gradually disappeared after placental delivery, with a typical rapid recovery of blood glucose homeostasis immediately, probably partly attributed to the secretion of hormones in the placenta [1,[8], [9], [10]]. On the other hand, the function of placenta may change adaptively with increasing maternal insulin resistance [5,11]. A study of early embryos found that the abnormal maternal metabolic milieu caused by obesity could change the transcriptome of placental progenitor cells in the ectoplacental cone (which is associated with later placental development) and that placental microvessel density was reduced at both mid and late gestation [12]. It is well known that during pregnancy, the placenta continuously undergoes high levels of vasculogenesis and angiogenesis to provide the fetus with the nutrients required for growth and development, suggesting the self-evident importance of the occurrence, maturation, and maintenance of vascular system for fetal development [13,14].

The determinants and pathogenic mechanisms of placental function affected by glucose intolerance during pregnancy are very complex and have not been fully revealed so far. To date, only a few studies have focused on the effect of glucose intolerance on placental angiogenesis, and the underlying mechanisms have been rarely explored. In recent years, Krüppel-like factors (KLFs), members of the zinc finger family of transcription factors, have received increasing attention as key regulators of endothelial cell biology. The regulation of KLF4 by physiologic stimuli (such as disturbed blood flow and inflammatory stimuli) was reported to mediate the changes of key endothelial targets, with KLF4 as an essential determinant of atherosclerosis [15,16]. However, the role of endothelial KLF4 in placental angiogenesis in the context of abnormal maternal metabolism has not yet been described. Therefore, this study aimed to explore the effect of maternal glucose tolerance deterioration in late pregnancy on placental angiogenesis and pregnancy outcome, and the decreased expression of KLF4 induced by high glucose levels was found to be an important cause of angiogenesis impairment.