Endothelial Estrogen Receptor Alpha Inhibits Plaque Inflammation in Both Sexes

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Immunology

Background:

• Atherosclerotic plaque inflammation is linked to myocardial infarction risk.
• Estrogen receptor (ER) function, particularly ER alpha (ERa), is implicated in sex-based differences in atherosclerosis, but its precise role in plaque inflammation remains unclear.

Purpose of the Study:

• To investigate the mechanistic role of ER alpha (ERa) in endothelial cell (EC) adhesion molecule expression and plaque inflammation in both sexes.
• To explore the interplay between ERa and the mineralocorticoid receptor (MR) in regulating inflammation.

Main Methods:

• Utilized low-density lipoprotein receptor (LDLR)-knockout mice with endothelial cell (EC)-specific ERa knockout, comparing them to ERa-intact littermates on a high-fat diet.
• Conducted in vitro studies using primary human ECs to assess ERa and ICAM1 expression and the effects of ERa knockdown.
• Investigated EC-specific MR knockout and combined EC-ERa/MR double-knockout mouse models.

Main Results:

• EC-specific ERa knockout increased plaque inflammation and ICAM1 expression in both male and female mice.
• Human female ECs exhibited higher ERa and lower ICAM1 expression than male ECs; ERa knockdown increased adhesion molecules in both sexes.
• Estrogen inhibited MR-induced ICAM1 expression in human ECs. In female mice, MR knockout had no effect, but combined ERa/MR knockout prevented inflammation upon ERa loss. In male mice, MR knockout reduced inflammation, and in double knockouts, MR and ERa effects on inflammation were balanced.

Conclusions:

• ER alpha (ERa) is crucial for regulating plaque inflammation in both sexes.
• In females, ERa inhibits MR-mediated ICAM1 upregulation, thereby reducing plaque inflammation.
• In males, plaque inflammation involves MR-driven ICAM1 expression counteracted by ERa's inhibitory effects.