학술논문
Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment
Clinical Research Article
Clinical Research Article
Document Type
Academic Journal
Author
Todd, Naomi; Mcnally, Ross; Alqudah, Abdelrahim; Jerotic, Djurdja; Suvakov, Sonja; Obradovic, Danilo; Hoch, Denise; Hombrebueno, Jose R.; Campos, Guillermo Lopez; Watson, Chris J.; Gojnic-Dugalic, Miroslava; Simic, Tatjana P.; Krasnodembskaya, Anna; Desoye, Gemot; Eastwood, Kelly-Ann; Hunter, Alyson J.; Holmes, Valerie A.; Mccance, David R.; Young, Ian S.; Grieve, David J.; Kenny, Louise C.; Garovic, Vesna D.; Robson, Tracy; Mcclements, Lana
Source
Journal of Clinical Endocrinology & Metabolism. January 2021, Vol. 106 Issue 1, p26, 16 p.
Subject
Language
English
ISSN
0021-972X
Abstract
Hypertensive disorders of pregnancy are a leading cause of maternal and neonatal morbidity and mortality (1). Preeclampsia, one of the most dangerous hypertensive disorders of pregnancy, develops after 20 weeks [...]
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 [greater than or equal to] 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. KeyWords: preeclampsia, angiogenesis, risk prediction, mesenchymal stem cell treatment, trophoblast cells, endothelial function
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 [greater than or equal to] 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. KeyWords: preeclampsia, angiogenesis, risk prediction, mesenchymal stem cell treatment, trophoblast cells, endothelial function