Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression

Cell Mol Biol Lett. 2025 Apr 4;30(1):41. doi: 10.1186/s11658-025-00720-y.

Abstract

Background: The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT.

Methods: In this study, apolipoprotein E-deficient (ApoE-/-) mice served as an atherosclerosis model, while human umbilical vascular endothelial cells (HUVECs) were used as cellular models. Protein levels were assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, and nucleic acid-protein interactions were evaluated using immunoprecipitation. The m6A modification status was determined by MeRIP, and cellular behaviors were analyzed through standard biochemical assays.

Results: Our results indicate that FSH induces EndMT both in vitro and in vivo. Additional investigation suggested that FSH upregulates the transcription factor Forkhead box protein M1 (FOXM1) at both protein and mRNA levels by enhancing the expression of AlkB homolog 5, RNA demethylase (ALKBH5). FSH reduces m6A modifications on FOXM1 through ALKBH5, leading to increased nascent transcript levels and mRNA stability of FOXM1. Dual-luciferase reporter assays highlighted cAMP-response element binding protein (CREB)'s essential function in facilitating the FSH-induced upregulation of ALKBH5.

Conclusions: These findings suggest that FSH promotes ALKBH5 expression, facilitates N6-methyladenosine (m6A) demethylation on FOXM1, and consequently, induces EndMT. This study elucidates the impact of FSH on plaque instability and provides insights into potential strategies to prevent acute coronary syndrome in postmenopausal women.

Keywords: ALKBH5; Endothelial to mesenchymal transition (EndMT); FOXM1; Follicle-stimulating hormone (FSH).

MeSH terms

  • AlkB Homolog 5, RNA Demethylase* / genetics
  • AlkB Homolog 5, RNA Demethylase* / metabolism
  • Animals
  • Apolipoproteins E / deficiency
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Endothelial-Mesenchymal Transition
  • Epithelial-Mesenchymal Transition* / drug effects
  • Female
  • Follicle Stimulating Hormone* / metabolism
  • Follicle Stimulating Hormone* / pharmacology
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Up-Regulation* / drug effects

Substances

  • Follicle Stimulating Hormone
  • AlkB Homolog 5, RNA Demethylase
  • Forkhead Box Protein M1
  • ALKBH5 protein, human
  • Apolipoproteins E