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

doi:10.1016/j.cell.2013.12.025

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

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

50 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 language	English (US)
Pages (from-to)	549-562
Number of pages	14
Journal	Cell
Volume	156
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2013.12.025
State	Published - Jan 30 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Goddard, L. M., Murphy, T. J., Org, T., Enciso, J. M., Hashimoto-Partyka, M. K., Warren, C. M., Domigan, C. K., McDonald, A. I., He, H., Sanchez, L. A., Allen, N. C., Orsenigo, F., Chao, L. C., Dejana, E., Tontonoz, P., Mikkola, H. K. A., & Iruela-Arispe, M. L. (2014). Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation. Cell, 156(3), 549-562. https://doi.org/10.1016/j.cell.2013.12.025

@article{eb59de552e59418aac5bd2cc59db000f,

title = "Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation",

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.",

author = "Goddard, {Lauren M.} and Murphy, {Thomas J.} and T{\"o}nis Org and Enciso, {Josephine M.} and Hashimoto-Partyka, {Minako K.} and Warren, {Carmen M.} and Domigan, {Courtney K.} and McDonald, {Austin I.} and Huanhuan He and Sanchez, {Lauren A.} and Allen, {Nancy C.} and Fabrizio Orsenigo and Chao, {Lily C.} and Elisabetta Dejana and Peter Tontonoz and Mikkola, {Hanna K.A.} and Iruela-Arispe, {M. Luisa}",

note = "Funding Information: The authors thank Kari Alitalo for providing the tie1 construct, Liman Zhao for mouse husbandry, and the Tissue Procurement Core Laboratory Shared Resource. This study was supported by grants from the National Institutes of Health (RO1HL74455-01 to M.L.I.-A., RO1HL097766 to H.K.A.M., and T32HL69766 to L.M.G.), the American Heart Association (AHA-11PRE7300043 to L.M.G.), the Iris Cantor-UCLA Women{\textquoteright}s Health Center (L.M.G.), the European Social Fund (Mobilitas grant MJD284 to T.O.), and the Leukemia and Lymphoma Society (5737-13 to T.O.). The UCLA Vector Core generated lentiviral vectors (supported by JCCC/P30 CA016042 and CURE/P30 DK041301). ",

year = "2014",

month = jan,

day = "30",

doi = "10.1016/j.cell.2013.12.025",

language = "English (US)",

volume = "156",

pages = "549--562",

journal = "Cell",

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number = "3",

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Goddard, LM, Murphy, TJ, Org, T, Enciso, JM, Hashimoto-Partyka, MK, Warren, CM, Domigan, CK, McDonald, AI, He, H, Sanchez, LA, Allen, NC, Orsenigo, F, Chao, LC, Dejana, E, Tontonoz, P, Mikkola, HKA & Iruela-Arispe, ML 2014, 'Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation', Cell, vol. 156, no. 3, pp. 549-562. https://doi.org/10.1016/j.cell.2013.12.025

TY - JOUR

T1 - Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation

AU - Goddard, Lauren M.

AU - Murphy, Thomas J.

AU - Org, Tönis

AU - Enciso, Josephine M.

AU - Hashimoto-Partyka, Minako K.

AU - Warren, Carmen M.

AU - Domigan, Courtney K.

AU - McDonald, Austin I.

AU - He, Huanhuan

AU - Sanchez, Lauren A.

AU - Allen, Nancy C.

AU - Orsenigo, Fabrizio

AU - Chao, Lily C.

AU - Dejana, Elisabetta

AU - Tontonoz, Peter

AU - Mikkola, Hanna K.A.

AU - Iruela-Arispe, M. Luisa

N1 - Funding Information: The authors thank Kari Alitalo for providing the tie1 construct, Liman Zhao for mouse husbandry, and the Tissue Procurement Core Laboratory Shared Resource. This study was supported by grants from the National Institutes of Health (RO1HL74455-01 to M.L.I.-A., RO1HL097766 to H.K.A.M., and T32HL69766 to L.M.G.), the American Heart Association (AHA-11PRE7300043 to L.M.G.), the Iris Cantor-UCLA Women’s Health Center (L.M.G.), the European Social Fund (Mobilitas grant MJD284 to T.O.), and the Leukemia and Lymphoma Society (5737-13 to T.O.). The UCLA Vector Core generated lentiviral vectors (supported by JCCC/P30 CA016042 and CURE/P30 DK041301).

PY - 2014/1/30

Y1 - 2014/1/30

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cell.2013.12.025

DO - 10.1016/j.cell.2013.12.025

M3 - Article

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AN - SCOPUS:84893469062

SN - 0092-8674

VL - 156

SP - 549

EP - 562

JO - Cell

JF - Cell

IS - 3

ER -

Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation

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