Immune regulation and lymphangiogenesis by lymphatic endothelial cells in the decidua in severe preeclampsia

Abstract

Lymphatic vasculature regulates lymphocyte trafficking and modulates adaptive immunity. Imbalanced immune cells at the maternal-fetal interface may contribute to severe preeclampsia (PE). Impaired placental lymphangiogenesis and immune dysregulation could contribute to PE but supporting evidence is limited. Here, we investigate the association between lymphangiogenesis and immune regulation in severe PE. First, we identified the presence of LYVE1-positive lymphatic vessels in the decidua, and then decidual lymphatic endothelial cells (dLECs) were isolated and cultured from chorioamniotic membranes obtained at cesarean section from women with PE (n = 15) and gestational age-matched controls (n = 15). The cells were identified by LYVE1, Prox1, and CD31 expression. Gene expression analysis showed the significant different gene expression profiles in PE compared to normal (lymphatic vessel development, immune cell trafficking and T-cell activation regulation). dLECs from PE pregnancies showed substantially reduced migration, adhesion, morphological differentiation, and decreased lymphatic sprouting in a 3D lymphatic ring assay compared with normal. Additionally, they exhibited low chemokine ligand 21 expression, impaired dendritic cell recruitment, and reduced Akt-eNOS-nitric oxide signaling, which suppresses decidual cytotoxic T-cell activation in decidua. Collectively, our findings suggest that impaired lymphatic vessel function and molecular alterations in the decidua may disrupt immune regulation and contribute to severe PE.