Protease-activated receptor 2 contributes to placental development and fetal growth in mice

Shu Yamakage; Yuji Oe; Akiyo Sekimoto; Hirofumi Obata; Miho Yasuta; Emiko Sato; Satoshi Kumakura; Hiroshi Sato; Junichi Sugawara; Sadayoshi Ito; Nobuyuki Takahashi

doi:10.1016/j.thromres.2020.06.039

Protease-activated receptor 2 contributes to placental development and fetal growth in mice

Shu Yamakage, Yuji Oe, Akiyo Sekimoto, Hirofumi Obata, Miho Yasuta, Emiko Sato, Satoshi Kumakura, Hiroshi Sato, Junichi Sugawara, Sadayoshi Ito, Nobuyuki Takahashi

PHA - Pharmacy

Tohoku University

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

2 Citations (Scopus)

Abstract

Background: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. Objective: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. Methods: PAR2^−/− or PAR2^+/+ mice in the ICR background were used. Female PAR2^−/− mice were mated with male PAR2^−/− mice, and female PAR2^+/+ mice were mated with male PAR2^+/+ mice to obtain PAR2^−/− and PAR2^+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. Results: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. Conclusion: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.

Original language	English
Pages (from-to)	173-179
Number of pages	7
Journal	Thrombosis Research
Volume	193
DOIs	https://doi.org/10.1016/j.thromres.2020.06.039
Publication status	Published - 2020 Sept

Keywords

Angiogenesis
Angiopoietin
Coagulation
Tissue factor

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10.1016/j.thromres.2020.06.039

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@article{70fc1fc00ec847c48ceb16b657973620,

title = "Protease-activated receptor 2 contributes to placental development and fetal growth in mice",

abstract = "Background: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. Objective: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. Methods: PAR2−/− or PAR2+/+ mice in the ICR background were used. Female PAR2−/− mice were mated with male PAR2−/− mice, and female PAR2+/+ mice were mated with male PAR2+/+ mice to obtain PAR2−/− and PAR2+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. Results: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. Conclusion: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.",

keywords = "Angiogenesis, Angiopoietin, Coagulation, Tissue factor",

author = "Shu Yamakage and Yuji Oe and Akiyo Sekimoto and Hirofumi Obata and Miho Yasuta and Emiko Sato and Satoshi Kumakura and Hiroshi Sato and Junichi Sugawara and Sadayoshi Ito and Nobuyuki Takahashi",

note = "Funding Information: We thank members of Tohoku University, Faculty of Pharmaceutical Sciences, for their assistance. Our work was supported by Grants-In-Aid from the Japan Society for the Promotion of Science (JSPS16J03192, 18K15993). S.Y. Y.O. A.S. H.O. M.Y. and E.S. performed the experiments. S.Y. Y.O. A.S. H.O. E.S. and N.T. analyzed data. S.Y. Y.O. and N.T. co-wrote the manuscript. S.K. J.S. H.S. and S.I. interpreted data and edited the manuscript. N.T. contributed to conception of research. The authors have no conflicts of interest to disclosure. Funding Information: We thank members of Tohoku University, Faculty of Pharmaceutical Sciences, for their assistance. Our work was supported by Grants-In-Aid from the Japan Society for the Promotion of Science ( JSPS16J03192 , 18K15993 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2020",

month = sep,

doi = "10.1016/j.thromres.2020.06.039",

language = "English",

volume = "193",

pages = "173--179",

journal = "Thrombosis Research",

issn = "0049-3848",

publisher = "Elsevier Ltd.",

}

TY - JOUR

T1 - Protease-activated receptor 2 contributes to placental development and fetal growth in mice

AU - Yamakage, Shu

AU - Oe, Yuji

AU - Sekimoto, Akiyo

AU - Obata, Hirofumi

AU - Yasuta, Miho

AU - Sato, Emiko

AU - Kumakura, Satoshi

AU - Sato, Hiroshi

AU - Sugawara, Junichi

AU - Ito, Sadayoshi

AU - Takahashi, Nobuyuki

N1 - Funding Information: We thank members of Tohoku University, Faculty of Pharmaceutical Sciences, for their assistance. Our work was supported by Grants-In-Aid from the Japan Society for the Promotion of Science (JSPS16J03192, 18K15993). S.Y. Y.O. A.S. H.O. M.Y. and E.S. performed the experiments. S.Y. Y.O. A.S. H.O. E.S. and N.T. analyzed data. S.Y. Y.O. and N.T. co-wrote the manuscript. S.K. J.S. H.S. and S.I. interpreted data and edited the manuscript. N.T. contributed to conception of research. The authors have no conflicts of interest to disclosure. Funding Information: We thank members of Tohoku University, Faculty of Pharmaceutical Sciences, for their assistance. Our work was supported by Grants-In-Aid from the Japan Society for the Promotion of Science ( JSPS16J03192 , 18K15993 ). Publisher Copyright: © 2020 Elsevier Ltd

PY - 2020/9

Y1 - 2020/9

N2 - Background: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. Objective: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. Methods: PAR2−/− or PAR2+/+ mice in the ICR background were used. Female PAR2−/− mice were mated with male PAR2−/− mice, and female PAR2+/+ mice were mated with male PAR2+/+ mice to obtain PAR2−/− and PAR2+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. Results: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. Conclusion: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.

AB - Background: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. Objective: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. Methods: PAR2−/− or PAR2+/+ mice in the ICR background were used. Female PAR2−/− mice were mated with male PAR2−/− mice, and female PAR2+/+ mice were mated with male PAR2+/+ mice to obtain PAR2−/− and PAR2+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. Results: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. Conclusion: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.

KW - Angiogenesis

KW - Angiopoietin

KW - Coagulation

KW - Tissue factor

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UR - http://www.scopus.com/inward/citedby.url?scp=85088313647&partnerID=8YFLogxK

U2 - 10.1016/j.thromres.2020.06.039

DO - 10.1016/j.thromres.2020.06.039

M3 - Article

C2 - 32717642

AN - SCOPUS:85088313647

SN - 0049-3848

VL - 193

SP - 173

EP - 179

JO - Thrombosis Research

JF - Thrombosis Research

ER -

Protease-activated receptor 2 contributes to placental development and fetal growth in mice

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Keywords

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