Progesterone Signaling in the Endothelium: The Role of Progesterone Receptor in Physiological Vascular Permeability and Leukocyte Trafficking

Goddard, Lauren



Progesterone is essential for all reproductive processes including cycling, embryo implantation and maintenance of pregnancy. The complex endometrial changes that occur in preparation for embryo implantation and subsequent gestation place unique functional demands on the uterine vasculature including the need for increased permeability and selective leukocyte transmigration. While these changes are assumed to be under progesterone control, the exact cellular and molecular regulation remains largely unknown. Here we identify endothelial progesterone receptor (PR) as a direct mediator of the vascular responses downstream of progesterone. Restricted expression of PR in the endothelium of veins and lymphatics ensures vessel-selectivity to progesterone signaling, and correlates with its biological function in the endometrial vasculature. Using both genetic ablation and overexpression models combined with physiological experimentation of PR in the vasculature, we were able to demonstrate that cell autonomous PR signaling in the endothelium mediates the vascular permeability response that precedes implantation. Mechanistically, we found that PR induces a NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates localized and sustained vascular permeability in response to progesterone. We also found that conditional deletion of PR from the endothelial compartment results in selective trafficking of macrophages and neutrophils into the uterus. Using unbiased transcriptome analysis in combination with a read-out of PR binding sites, we determined that PR directly downregulates the expression of the endothelial-leukocyte adhesion molecules VCAM-1 and E-selectin, as well as a select group of cytokines/chemokines including, IL-6, IL-8, CXCL2/3, and CXCL1. Thus endothelial PR enables the discrimination of leukocyte subpoulations through selective expression of molecules important for leukocyte transmigration. Together, this work has identified novel functions and molecular targets of PR In the vasculature, with a number of important implications to our current assessment of the physiological and therapeutic effects of progesterone.