Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment

Naomi Todd; Ross McNally; Abdelrahim Alqudah; Djurdja Jerotic; Sonja Suvakov; Danilo Obradovic; Denise Hoch; Jose R. Hombrebueno; Guillermo Lopez Campos; Chris J. Watson; Miroslava Gojnic-Dugalic; Tatjana P. Simic; Anna Krasnodembskaya; Gernot Desoye; Kelly-Ann Eastwood; Alyson J. Hunter; Valerie A. Holmes; David R. McCance; Ian S. Young; David J. Grieve; Louise C. Kenny; Vesna D. Garovic; Tracy Robson; Lana McClements

doi:10.1210/clinem/dgaa403

Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment

Naomi Todd, Ross McNally, Abdelrahim Alqudah, Djurdja Jerotic, Sonja Suvakov, Danilo Obradovic, Denise Hoch, Jose R. Hombrebueno, Guillermo Lopez Campos, Chris J. Watson, Miroslava Gojnic-Dugalic, Tatjana P. Simic, Anna Krasnodembskaya, Gernot Desoye, Kelly-Ann Eastwood, Alyson J. Hunter, Valerie A. Holmes, David R. McCance, Ian S. Young, David J. GrieveLouise C. Kenny, Vesna D. Garovic, Tracy Robson, Lana McClements

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Abstract

Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.

Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.

Design and Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.

Settings and Participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.

Main Outcome Measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.

Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis.

Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

Original language	English
Pages (from-to)	26-41
Number of pages	16
Journal	The Journal of Clinical Endocrinology & Metabolism
Volume	106
Issue number	1
Early online date	27 Nov 2020
DOIs	https://doi.org/10.1210/clinem/dgaa403
Publication status	Published - 02 Jan 2021

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Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment
Copyright 2020 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.6 MBLicence: CC BY

The role of FKBPL in diabetes and associated cardiovascular health
Alqudah, A. (Author), Grieve, D. (Supervisor), Lyons, T. (Supervisor) & McClements, L. (Supervisor), Dec 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Ian Young
- I.Youngqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Centre for Public Health
- Institute for Global Food Security
Person: Academic

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Todd, N., McNally, R., Alqudah, A., Jerotic, D., Suvakov, S., Obradovic, D., Hoch, D., Hombrebueno, J. R., Campos, G. L., Watson, C. J., Gojnic-Dugalic, M., Simic, T. P., Krasnodembskaya, A., Desoye, G., Eastwood, K.-A., Hunter, A. J., Holmes, V. A., McCance, D. R., Young, I. S., ... McClements, L. (2021). Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment. The Journal of Clinical Endocrinology & Metabolism, 106(1), 26-41. https://doi.org/10.1210/clinem/dgaa403

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title = "Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment",

abstract = "Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and Participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.",

author = "Naomi Todd and Ross McNally and Abdelrahim Alqudah and Djurdja Jerotic and Sonja Suvakov and Danilo Obradovic and Denise Hoch and Hombrebueno, {Jose R.} and Campos, {Guillermo Lopez} and Watson, {Chris J.} and Miroslava Gojnic-Dugalic and Simic, {Tatjana P.} and Anna Krasnodembskaya and Gernot Desoye and Kelly-Ann Eastwood and Hunter, {Alyson J.} and Holmes, {Valerie A.} and McCance, {David R.} and Young, {Ian S.} and Grieve, {David J.} and Kenny, {Louise C.} and Garovic, {Vesna D.} and Tracy Robson and Lana McClements",

year = "2021",

month = jan,

day = "2",

doi = "10.1210/clinem/dgaa403",

language = "English",

volume = "106",

pages = "26--41",

journal = "The Journal of Clinical Endocrinology & Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "1",

}

Todd, N, McNally, R, Alqudah, A, Jerotic, D, Suvakov, S, Obradovic, D, Hoch, D, Hombrebueno, JR, Campos, GL , Watson, CJ, Gojnic-Dugalic, M, Simic, TP, Krasnodembskaya, A, Desoye, G, Eastwood, K-A, Hunter, AJ, Holmes, VA, McCance, DR, Young, IS , Grieve, DJ, Kenny, LC, Garovic, VD, Robson, T & McClements, L 2021, 'Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment', The Journal of Clinical Endocrinology & Metabolism, vol. 106, no. 1, pp. 26-41. https://doi.org/10.1210/clinem/dgaa403

TY - JOUR

T1 - Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment

AU - Todd, Naomi

AU - McNally, Ross

AU - Alqudah, Abdelrahim

AU - Jerotic, Djurdja

AU - Suvakov, Sonja

AU - Obradovic, Danilo

AU - Hoch, Denise

AU - Hombrebueno, Jose R.

AU - Campos, Guillermo Lopez

AU - Watson, Chris J.

AU - Gojnic-Dugalic, Miroslava

AU - Simic, Tatjana P.

AU - Krasnodembskaya, Anna

AU - Desoye, Gernot

AU - Eastwood, Kelly-Ann

AU - Hunter, Alyson J.

AU - Holmes, Valerie A.

AU - McCance, David R.

AU - Young, Ian S.

AU - Grieve, David J.

AU - Kenny, Louise C.

AU - Garovic, Vesna D.

AU - Robson, Tracy

AU - McClements, Lana

PY - 2021/1/2

Y1 - 2021/1/2

N2 - Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and Participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

AB - Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.Design and Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.Settings and Participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

U2 - 10.1210/clinem/dgaa403

DO - 10.1210/clinem/dgaa403

M3 - Article

C2 - 32617576

SN - 0021-972X

VL - 106

SP - 26

EP - 41

JO - The Journal of Clinical Endocrinology & Metabolism

JF - The Journal of Clinical Endocrinology & Metabolism

IS - 1

ER -

Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment

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Student theses

The role of FKBPL in diabetes and associated cardiovascular health

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Ian Young

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