Aim: Menopause and subsequent estrogen deficiency correlate with the development of atherosclerosis and cardiovascular diseases in women. However, the relationship between estrogen deficiency and development of atherosclerosis with inflammatory infiltrates is not fully understood. We sought to determine whether perimenopausal women (PMW) exhibited T cell dysfunction related to the expression of adhesion molecules and accelerated endothelial cell (EC) apoptosis.
Methods: Fresh CD4 T cells were isolated from 48 PMW and 54 healthy control women with regular menstrual cycles (CW), and investigated cytotoxicity to ECs by apoptosis assay. The adhesion molecules on CD4 T cells were examined by flow cytometry. CD4 T cell rolling and adhesion on ECs were analyzed by adhesion assay under laminar flow.
Results: CD4 T cells from PMW with low estradiol levels induced significant EC apoptosis (P = 0.0152). Furthermore, cytotoxic CD4 T cells from PMW strongly expressed P-selectin glycoprotein ligand-1 (PSGL-1) and integrin β2 (P < 0.0001 and P = 0.0285, respectively) but not L-selectin or integrin αM when compared to CD4 T cells from CW. Estradiol levels negatively correlated with only PSGL-1 expression (R = -0.781, P = 0.0002), and estradiol treatments inhibited both PSGL-1 expression (P = 0.0133) and T cell-induced EC apoptosis (P = 0.018). An estrogen receptor antagonist inhibited these effects of estradiol (P = 0.0355 and P = 0.0097, respectively). Moreover, PSGL-1 expression correlated with T cell adhesion to ECs under laminar flow conditions (R = 0.636, P = 0.0355) and with EC apoptosis (R = 0.614, P = 0.0196). PSGL-1 specific antibodies effectively suppressed T cell adhesion (P = 0.0057) and EC apoptosis (P = 0.001) indicating that CD4 T cell-mediated EC apoptosis depended on PSGL-1 adhesion in PMW.
Conclusions: PSGL-1-expressing cytotoxic CD4 T cells are abundant in PMW with low estradiol levels may contribute to T cell-mediated atherosclerotic development.