Hemodynamic Regulation of Androgen Receptor‐dependent Inflammatory Signaling

Abstract

The correlation between timing of vascular disease in women and decreased production of estrogen after menopause suggests that circulating androgens promote vascular inflammation in the absence of protective estrogens. We hypothesized that androgen (R1881) stimulates androgen receptor (AR) in human endothelial cells to induce inflammatory signaling in a manner that is modulated by an atheroprotective shear stress (SS) profile. R1881 treatment for 24 h caused 2‐fold upregulation of AR protein expression and increased AR nuclear localization, whereas steady unidirectional SS (15 dyn/cm2) for 24 h caused 1.2‐fold downregulation of expression and nearly 3‐fold decrease in nuclear localization. Atheroprotective SS prevented AR upregulation regardless of whether cells were pretreated with or sheared in the presence of R1881. R1881 treatment for 48 h induced a nearly 2‐fold increase in VCAM‐1 expression, suggesting that ligand‐activated AR promotes inflammatory signaling. SS abrogated the effects of R1881. These data are the first evidence that SS and ligand differentially regulate AR to modulate inflammatory signaling in human endothelial cells. Supported by NIH grant HL071958 and a UVa CVRC Partners Award.