Emerging roles of GPER in diabetes and atherosclerosis

• The 7-transmembrane G protein-coupled estrogen receptor (GPER) contributes to vascular tone and blood pressure.
• GPER deletion augments endothelium-dependent vasoconstriction and the activity of vasoactive peptides.
• Mice lacking GPER develop visceral obesity, increased LDL cholesterol levels, a prodiabetic metabolic profile, and generalized inflammation.
• GPER regulates pancreatic hormone secretion (including insulin) and modulates the insulin responsiveness of peripheral tissues.
• Loss of GPER accelerates atherogenesis and vascular inflammation in an estrogen-dependent fashion. Both pathologies can be alleviated using GPER-targeted drugs.

The G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings on its roles in obesity, diabetes, and atherosclerosis, including GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed.