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

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Biology

Background:

• Atherosclerosis incidence increases post-menopause, with elevated follicle-stimulating hormone (FSH) accelerating its progression.
• Endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, a key factor in acute coronary syndrome.
• The specific link between FSH and EndMT has remained largely uncharacterized.

Purpose of the Study:

• To investigate the influence of FSH on EndMT.
• To elucidate the molecular mechanisms by which FSH may modulate EndMT in the context of atherosclerosis.

Main Methods:

• Utilized apolipoprotein E-deficient (ApoE-/-) mice as an atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) as a cellular model.
• Assessed protein and mRNA levels using immunochemical techniques and RT-qPCR.
• Evaluated m6A modification status via MeRIP and nucleic acid-protein interactions using immunoprecipitation.

Main Results:

• Follicle-stimulating hormone (FSH) was found to induce EndMT both in vitro and in vivo.
• FSH upregulates Forkhead box protein M1 (FOXM1) by enhancing AlkB homolog 5, RNA demethylase (ALKBH5) expression.
• FSH reduces m6A modifications on FOXM1 via ALKBH5, increasing FOXM1 transcript levels and stability, a process facilitated by CREB.

Conclusions:

• FSH promotes ALKBH5 expression, leading to N6-methyladenosine (m6A) demethylation of FOXM1 and subsequent induction of EndMT.
• This mechanism highlights FSH's role in promoting plaque instability.
• Findings offer potential therapeutic targets for preventing acute coronary syndrome in postmenopausal women.