Endothelial dysfunction in diabesity: role of sex hormones

Abstract

[eng] Diabesity, the combination of diabetes and obesity and their close relationship, is often deemed as the world’s largest epidemic. Increased adiposity has several cardiovascular consequences, and oestrogen has been shown to have beneficial effects on the cardiovascular system; however, its exact signalling mechanism has yet to be elucidated in many cases. Determining via which receptor oestrogen signals in endothelial cells is of great interest, since endothelial dysfunction is considered an initial step in atherosclerosis, and can give further insight into cardiovascular pathologies and development of highly personalised therapies. For this reason, glucolipotoxicity was induced in cultured human endothelial cells by treatment with high glucose and palmitate to represent the diabetic and obese condition, and oestrogen signalling was analysed looking specifically at responses when signalling via each receptor separately. In general, 17β-oestradiol (E2) ameliorated endothelial dysfunction when signalling via its membrane-bound receptor GPER; however, signalling via nuclear receptors ERα or ERβ appeared to increase expression of markers of endothelial dysfunction, such as ICAM-1 and VCAM-1, indicating that E2’s beneficial effects may be associated with GPER signalling. However, E2’s role in glucolipotoxicity may also be the contrary. E2 signalling via ERα or ERβ appears to play a detrimental role, as it also aggravated ROS production, as well as increased E-selectin expression. Altogether, this work demonstrates that E2’s beneficial effects may be associated via GPER signalling and also highlights the importance of exploring E2 receptors and their implication in endothelial dysfunction.