Progesterone Receptor in the Vascular Endothelium Triggers Physiological Uterine Permeability Preimplantation

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation. [Display omitted] •Endothelial PR mediates local vascular permeability in response to progesterone•Restricted expression of PR ensures organ and vessel selectivity to progesterone•PR activation of NR4A1 (Nur77/TR3) triggers barrier instability in the endothelium Before implantation, uterine vessels become leaky, providing nutrients to the embryo. This study now shows that this is orchestrated by the progesterone receptor and the orphan nuclear receptor NR4A1, which regulates junctional proteins locally and in a timely manner.