Estrogen is a modulator of Tumor Necrosis Factor responses in the human vascular endothelium

Abstract

Premenopausal women are protected against cardiovascular diseases compared to age‐matched men. However, these women are also at an increased risk of inflammatory and autoimmune diseases. Higher circulating levels of estrogen may exert an immunomodulatory effect. Given this background, we hypothesized that chronic estrogen exposure alters the endothelial response to inflammatory stimulation. We treated confluent monolayers of second passage human umbilical vein endothelial cells (HUVECs) for 24 hours with physiologically relevant doses of 17‐beta estradiol (E2) prior to stimulation with the pro‐inflammatory cytokine tumor necrosis factor (TNF). We found that E2 treatment increased TNFR2 levels without affecting TNFR1. There was a trend towards aggravation of TNF induced upregulation of leukocyte adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) on E2 pre‐treatment. There was also a change in the activation profile of nuclear factor kappa B on TNF stimulation between E2 treated and control cells. In summary, chronic E2 treatment altered the endothelial responses to TNF stimulation, involving modulation at the levels of receptors, transcriptional pathways and adhesion molecule expression. This work provides a better understanding of the interplay between estrogen and the endothelial inflammatory response in health and disease.