Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation

Lauren M. Goddard, Thomas J. Murphy, Tönis Org, Josephine M. Enciso, Minako K. Hashimoto-Partyka, Carmen M. Warren, Courtney K. Domigan, Austin I. McDonald, Huanhuan He, Lauren A. Sanchez, Nancy C. Allen, Fabrizio Orsenigo, Lily C. Chao, Elisabetta Dejana, Peter Tontonoz, Hanna K.A. Mikkola, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)549-562
Number of pages14
JournalCell
Volume156
Issue number3
DOIs
StatePublished - Jan 30 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation'. Together they form a unique fingerprint.

Cite this