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.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Lauren M
LM
Goddard
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Thomas J
TJ
Murphy
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Tönis
T
Org
Division of Neonatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Josephine M
JM
Enciso
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Minako K
MK
Hashimoto-Partyka
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Carmen M
CM
Warren
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Courtney K
CK
Domigan
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Austin I
AI
McDonald
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Huanhuan
H
He
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Lauren A
LA
Sanchez
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Nancy C
NC
Allen
IFOM, Foundation FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Fabrizio
F
Orsenigo
Department of Pathology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Lily C
LC
Chao
IFOM, Foundation FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Elisabetta
E
Dejana
Department of Pathology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Peter
P
Tontonoz
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Hanna K A
HK
Mikkola
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: arispe@mcdb.ucla.edu.
M Luisa
ML
Iruela-Arispe
D000818:Animals; D002199:Capillary Permeability; D004717:Endometrium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D014599:Uterus / Q000378:metabolism*
C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1