PT  - JOURNAL ARTICLE
AU  - Andrea Cignarella
AU  - Chiara Bolego
AU  - Valeria Pelosi
AU  - Clara Meda
AU  - Andrée Krust
AU  - Christian Pinna
AU  - Rosa Maria Gaion
AU  - Elisabetta Vegeto
AU  - Adriana Maggi
TI  - Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes
AID  - 10.1124/jpet.108.143511
DP  - 2009 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 174--182
VI  - 328
IP  - 1
4099  - http://jpet.aspetjournals.org/content/328/1/174.short
4100  - http://jpet.aspetjournals.org/content/328/1/174.full
SO  - J Pharmacol Exp Ther2009 Jan 01; 328
AB  - Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ERα and ERβ-selective agonists 4,4′,4′′-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ERα attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17β-estradiol to aortic tissues from ERβ- but not ERα-knockout mice. These findings suggest a possible role for ERα-selective ligands in reducing vascular inflammatory responses under normo- and hyperglycemic conditions. The American Society for Pharmacology and Experimental Therapeutics