Suppressed G ‐protein‐coupled receptor kinase 2 activity protects female diabetic‐mouse aorta against endothelial dysfunction

Aim Pre‐menopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Previously, we noted in mice that G‐protein‐coupled receptor kinase 2 ( GRK 2) negatively regulates the A kt/e NOS pathway in male diabetic aortas and that endothelial function via the A kt/e NOS pathway is less affected in female diabetic aortas. The cellular mechanisms underlying these sex differences remain unclear. We aimed to investigate the ways in which GRK 2 might modulate vascular functions in male and female diabetic mice ( DM ). Methods Vascular functions were examined in aortic rings. GRK 2, β‐arrestin 2 and A kt/e NOS ‐signalling‐pathway protein levels and activities were assayed by W estern blotting. Results Phenylephrine‐induced contraction was greater, while both clonidine‐induced and insulin‐induced relaxations were weaker (vs. male controls), in aortas from male type 2 DM , suggesting impairments of the A kt/e NOS pathway and α‐adrenoceptor function. GRK 2‐inhibitor reversed only the impairment in A kt/e NOS ‐pathway‐mediated relaxation in male DM . Increases in GRK 2 activity, GRK 2 expression in the membrane, plasma A ng II and systolic blood pressure were seen in male DM (vs. male controls) but not in female DM ; these increases were attenuated by GRK 2‐inhibitor treatment. Repeatedly obtaining clonidine concentration‐response curves led to reduced relaxation in male and in female DM aortas, indicating similar desensitization between female DM and male DM . This effect was reversed by GRK 2‐inhibitor in both sexes. Conclusion GRK 2 plays a key role in modulating the aortic vasodilator effect of clonidine by selectively affecting the A kt/e NOS pathway. This action of GRK 2 is more powerful in male than in female DM .