Impact of the G protein-coupled estrogen receptor on endothelial derived arterial stiffening
"Cardiovascular disease is the leading cause of death for men and women in the United States. Arterial stiffness is an early indicator of hypertension that is associated with a change in the extracellular matrix composition leading to a decrease in vessel elasticity and increased cardiac afterload. In endothelial cells, the G protein-coupled estrogen receptor (GPER) activates endothelial nitric oxide synthase to counteract vasoconstriction and vascular remodeling. However, the interaction between endothelial GPER and arterial stiffening remains unknown. Here, we investigated the impact of chronic nitric oxide deficiency on pulse wave velocity, an in vivo measurement of arterial stiffness, and vascular structure and the role of GPER. A cohort composed of male wild-type and GPER knockout mice were chronically treated with a nitric oxide synthase inhibitor, N(G)-Nitro-L-arginine methyl ester hydrochloride (L-NAME), for three weeks. Pre- and post-treatment blood pressures were collected via tail-cuff plethysmography, ultrasound imaging was used to monitor pulse wave velocity, and pressure myography of the mesenteric artery ex vivo was used to assess vessel reactivity and structure. We found no change in blood pressure or mesenteric wall thickness over the course of L-NAME treatment. Pulse wave velocity significantly increased in response to L-NAME in wild-type mice but not in GPER knockout mice. Both L-NAME treatment and genetic deletion of GPER significantly increased myogenic tone. Interestingly, L-NAME treatment in GPER knockout mice reduced rather than exacerbated the myogenic response. These results provide evidence of the complicated role of GPER and nitric oxide in endothelial-mediated responses. Further testing is needed to understand estrogen's effect on endothelial dysfunction; the results of which could reveal important therapeutic targets. "