Progesterone Receptor in the Vascular Endothelium Triggers Physiological Uterine Permeability Preimplantation

Abstract

Summary Vascular permeability is frequently associated with inflammation and triggered by a cohort of secreted permeability factors such as VEGF. Here we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Both global and endothelial-specific deletion of PR block 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 ChIP-sequencing revealed that PR induces a 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 to embryo implantation.

Transcriptional Profiling of Human Endocervical Tissues Reveals Distinct Gene Expression in the Follicular and Luteal Phases of the Menstrual Cycle1

“…In contrast, genes upregulated in the luteal phase fell into distinct categories that were associated with inflammation, angiogenesis, chromatin modification, etc. This is not surprising as the luteal phase or progesterone itself promotes a secretory phenotype that is associated with increased vascular permeability and angiogenesis in the endometrium [33][34][35] which is contiguous to the endocervix. Recently, it was reported that proteins of the cervicovaginal fluid differed between the follicular and luteal phases [36].…”

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

“…The induction of PDK4 by progesterone, however, was fully blocked in the presence of mifepristone, indicating that the induction is progesterone receptor-mediated (Figure 4E). Data culled from chromatin immunoprecipitation sequencing (ChipSeq) experiments 20 demonstrated that the progesterone receptor binds directly to the PDK4 promoter as well as a region approximately 10kb upstream, and receptor binding was markedly increased by the presence of progesterone (Online Figure IVF). ENCODE data 21 demonstrates that both of these regions are hypersensitive to DNAseI digestion, and contain a high amount of histone acetylation at H3K27, indicating high transcriptional regulatory activity at both sites.…”

Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells

“…17 Accumulating evidence supports the involvement of human chorionic gonadotropin (hCG) in the function and differentiation of immune cells; in turn, the tissue-resident immune cells, along with hormones, positively regulate the uterine microenvironment and embryo implantation. 17 Accumulating evidence supports the involvement of human chorionic gonadotropin (hCG) in the function and differentiation of immune cells; in turn, the tissue-resident immune cells, along with hormones, positively regulate the uterine microenvironment and embryo implantation.…”