Diabetes Undermines Estrogen Control of Inducible Nitric Oxide Synthase Function in Rat Aortic Smooth Muscle Cells Through Overexpression of Estrogen Receptor-β

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Abstract
Background— Previous reports from our group have shown that 17β-estradiol reduces the synthesis and activity of inducible nitric oxide synthase (iNOS) in rat aortic smooth muscle cells (SMC) in response to inflammatory mediators. In this study, we investigated the effect of 17β-estradiol on iNOS function in aortic SMC from streptozotocin-diabetic rats. Methods and Results— Comparative analysis of NO release and of iNOS mRNA and protein content after 24-hour stimulation with a cytokine mixture revealed milder iNOS activation in diabetic than in control SMC. Furthermore, 17β-estradiol dose-dependently blocked iNOS synthesis and activity in control but not in diabetic SMC. The defective estrogen response in diabetic SMC at 24 hours could not be attributed to reduced expression of estrogen receptors (ER). In fact, mRNA and protein levels of ERα and, to a greater extent, of ERβ, were increased in diabetic compared with nondiabetic SMC. Cytokines decreased ERα and ERβ expression in both groups. However, 17β-estradiol dose-dependently restored the expression of ERα but further downregulated that of ERβ, indicating a differential regulation of ER isoforms. Conclusions— Estrogenic control of iNOS was impaired in diabetic SMC. This was associated with a larger increase of ERβ than of ERα protein, whereas 17β-estradiol regulated the two isoforms in an opposite fashion. Thus, modifications in the estrogen modulation of iNOS and in the expression pattern of ER may be involved in diabetic vascular dysfunction.