Mtnr1b deletion disrupts placental angiogenesis through the VEGF signaling pathway leading to fetal growth restriction

• Published in: Pharmacological research 2024-08, Vol.206, p.107290, Article 107290
• Main Authors: Wang, Likai, Han, Qi, Yan, Laiqing, Ma, Xiao, Li, Guangdong, Wu, Hao, Liu, Yunjie, Chen, Huiling, Ji, Pengyun, Wang, Bingyuan, Zhang, Ran, Liu, Guoshi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; IUGR; Melatonin; Melatonin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; MTNR1B; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; Oxidative Stress; p-STAT3; Placenta - blood supply; Placenta - metabolism; Placental angiogenesis; Pregnancy; Receptor, Melatonin, MT1 - genetics; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - genetics; Receptor, Melatonin, MT2 - metabolism; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Swine; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107290

The placenta, as a “transit station” between mother and fetus, has functions delivering nutrients, excreting metabolic wastes and secreting hormones. A healthy placenta is essential for fetal growth and development while the melatonergic system seems to play a critical physiological role in this organ since melatonin, its synthetic enzymes and receptors are present in the placenta. In current study, Mtnr1a and Mtnr1b knockout mice were constructed to explore the potential roles of melatonergic system played on the placental function and intrauterine growth retardation (IUGR). The result showed that Mtnr1a knockout had little effect on placental function while Mtnr1b knockout reduced placental efficiency and increased IUGR. Considering the extremely high incidence of IURG in sows, the pregnant sows were treated with melatonin. This treatment reduced the incidence of IUGR. All the evidence suggests that the intact melatonergic system in placenta is required for its function. Mechanistical studies uncovered that Mtnr1b knockout increased placental oxidative stress and apoptosis but reduced the angiogenesis. The RNA sequencing combined with histochemistry study identified the reduced angiogenesis and placental vascular density in Mtnr1b knockout mice. These alterations were mediated by the disrupted STAT3/VEGFR2/PI3K/AKT pathway, i.e., Mtnr1b knockout reduced the phosphorylation of STAT3 which is the promotor of VEGFR2. The downregulated VEGFR2 and its downstream elements of PI3K and AKT expressions, then, jeopardizes the angiogenesis and placental development. [Display omitted] •Mtnr1a knockout has little effect on placental function, while Mtnr1b knockout reduces placental efficiency and increases IUGR.•Knockout of the Mtnr1b resulted in increased levels of apoptosis and oxidative stress in placental tissue.•Treatment of pregnant sows with melatonin can increase the birth weight of piglets and reduce the incidence of IUGR.•Melatonergic system can regulate fetal growth by regulating the process of placental angiogenesis.•Melatonin activates its MT2 receptor, stimulates the STAT3/VEGFR2 pathway, and promotes placental angiogenesis.