Hypoxic trophoblasts secreted exosomes promote autophagy through TINCR to impair angiogenesis and drive preeclampsia

Abstract Pathological hypoxia/oxidative stress of placenta is a major cause in preeclampsia. Autophagy dysregulation has recently been linked to aberrant placental vascular function in preeclampsia [1, 2] while the underlying mechanisms remain unknown. Here, we found exosomal TINCR derived from trophoblasts exposed to hypoxia-oxidative stress induced placental vascular dysfunction through evoking excessive autophagic activation of endothelial cells related to preeclampsia. Specifically, umbilical cord serum- and plasma-derived exosomal TINCR levels were elevated in preeclampsia determined by microarray-based transcript analyses and qRT-PCR, which may be caused by trophoblasts releasing exosomes containing TINCR into circulation under pathological hypoxia conditions of the placenta. These exosomal TINCR impaired placental vascular function by promoting excessive autophagy of endothelial cells involved in preeclampsia-like symptoms both in vivo and in vitro. In contrast, the autophagy inhibitor hydroxychloroquine (HCQ) partially reversed exosomal TINCR's effect on placental vascular dysfunction and preeclampsia symptoms. Mechanistically, TINCR promoted autophagy in endothelial cells by regulating miR-424/ ATG5 axis as a competing endogenous RNA. Therefore, preeclampsia was associated with the overactivation of endothelial cell autophagy by trophoblast-derived exosomal TINCR in regulating placental vascular function, indicating that targeting autophagy such as HCQ is a novel strategy for preeclampsia treatment.