Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment

J Clin Endocrinol Metab. 2021 Jan 1;106(1):26-41. doi: 10.1210/clinem/dgaa403.

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.

Keywords: angiogenesis; endothelial function; mesenchymal stem cell treatment; preeclampsia; risk prediction; trophoblast cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / analysis
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hyaluronan Receptors / analysis
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / physiology*
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells / physiology
  • Molecular Targeted Therapy / methods
  • Neovascularization, Pathologic / diagnosis
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / therapy
  • Pre-Eclampsia* / diagnosis
  • Pre-Eclampsia* / genetics
  • Pre-Eclampsia* / therapy
  • Pregnancy
  • Prognosis
  • Risk Assessment
  • Signal Transduction / genetics
  • Tacrolimus Binding Proteins / analysis
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / physiology*
  • Young Adult

Substances

  • Biomarkers
  • CD44 protein, human
  • FKBPL protein, human
  • Hyaluronan Receptors
  • Tacrolimus Binding Proteins