PT  - JOURNAL ARTICLE
AU  - Stephanie Gehrs
AU  - Moritz Jakab
AU  - Ewgenija Gutjahr
AU  - Zuguang Gu
AU  - Dieter Weichenhan
AU  - Carolin Mogler
AU  - Matthias Schlesner
AU  - Christoph Plass
AU  - Hellmut G. Augustin
AU  - Katharina Schlereth
TI  - Endothelial Dnmt3a controls placenta vascularization and function to support fetal growth
AID  - 10.1101/2022.07.28.501807
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.28.501807
4099  - http://biorxiv.org/content/early/2022/07/29/2022.07.28.501807.short
4100  - http://biorxiv.org/content/early/2022/07/29/2022.07.28.501807.full
AB  - The fetoplacental capillary network is of vital importance for proper nourishment during early development. Inadequate maternal-fetal circulation has emerged as one of the main pathophysiological features of placental insufficiency. Meta-analysis of human placental endothelial cells (EC) revealed that downregulation of the de novo DNA methyltransferase 3A (DNMT3A) is associated with preeclampsia. However, mechanistic insights into functional consequences of altered DNA methylation patterns during placental vascular development remain elusive. Here, we investigated the role of Dnmt3a in the vasculature during murine placenta development. Spatial and temporal expression analyses revealed an induction of Dnmt3a in the mature labyrinth layer. The global and endothelium-specific loss (ECKO) of Dnmt3a resulted in reduced placental vascularization and fetal growth restriction. EC deleted for Dnmt3a demonstrated extensive loss of DNA methylation, particularly close to angiogenesis related genes. Loss of DNA methylation decreased the angiogenic capacity of EC in vitro and in vivo. Collectively, these data identify DNMT3A as the main DNA methyltransferase in the human and murine placental vasculature and characterize its importance for physiological endothelial function. The Dnmt3a-dependent regulation of genes related to placenta insufficiency validates Dnmt3a ECKO mice as an epigenetically driven mouse model of placenta insufficiency with potential translational relevance.Competing Interest StatementThe authors have declared no competing interest.