Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ERβ) in the vascular dysfunction in female type 1 diabetic rats

Aims: Inflammation is involved in diabetes-related vascular dysfunction. Estrogen receptor ESR2/ER beta induces the expression of inducible nitric oxide (NO) synthase (iNOS) and inflammation. The present study investigated the effect of alloxan-induced type 1 diabetes on the iNOS and ESR2 expression and the effect of the chronic iNOS inhibition on the vascular smooth muscle dysfunction in diabetic female rats. In addition, we evaluated the involvement of ESR2 in iNOS expression. Main methods: Alloxan-induced diabetic female rats were treated or not with iNOS inhibitor (L-NIL). iNOS and ESR2 immunostaining, S-nitrosylated proteins and IL-1 beta protein expression in aorta and plasmatic NO levels were analyzed. Contractile response to noradrenaline was analyzed in endothelium-denuded aorta. iNOS mRNA expression was analyzed in isolated aortic smooth muscle cells (ASMCs) of female rats, incubated with 22 mM glucose and an ESR2 antagonist. Key findings: Aortic iNOS and ESR2 immunostaining, S-nitrosylated proteins, IL-1 beta protein expression and plasmatic NO levels were all increased, whereas noradrenaline-induced contraction was reduced in aorta of diabetic female rats. With the exception of iNOS and ESR2 immunostaining, all these parameters were corrected by L-NIL treatment. High glucose increased iNOS mRNA expression in ASMCs, which was reduced by an ESR2 antagonist. Significance: We demonstrated that increased iNOS-NO contributed to the impairment of the contractile response of aortic smooth muscle cells in female type 1 diabetic rats and that increased expression of iNOS may involve the participation of ESR2/ER beta.